Research Models

Parkinson's Disease

Progress in Parkinson's disease research and therapeutic development depends on robust preclinical models, including rodent models. By organizing information related to the characterization of selected PD models, this resource conveys what is known about each one and facilitates comparison of phenotypes. This resource was created in collaboration with The Michael J. Fox Foundation (MJFF) as part of its commitment to make PD models more accessible and accelerate PD research.

The Parkinson's disease models were selected by experts at The Michael J. Fox Foundation (MJFF).

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32 Models

Mouse Models (26)
	Name	Other Names	Strain Name	Genetic Background	Gene	Mutation	Modification Info	Modification	Disease	Neuropathology	Behavior/Cognition	Other Phenotype	Availability	Primary Paper	Visualization
	Atp13a2-flox Mouse	<p>-</p>, <p>Atp13a2 null</p>, <p>Atp13a2 KO</p>	Atp13a2^tm1.1Wtd/J	Mixed C57BL6/129	Atp13a2		In this floxed mouse model, one loxP site is present upstream exon 2 and the second loxP site is present downstream exon 3 of the Atp13a2 gene. It was generated using homologous recombination of a targeting vector electroporated into B6/129 embryonic stem cells, with the aid of an FRT-flanked neomycin resistance cassette that was subsequently removed.	Atp13a2: Knock-Out	Parkinson's Disease	Adult-onset Atp13a2 KO in the ventral midbrain (via AAV-Cre delivery) resulted in neuropathology, including dopaminergic neuronal degeneration in the SN, which was not observed in germline Atp13a2 KO mice.	Motor function partially impaired in germline Atp13a2 KO mice, including defects on the open-field and tail suspension tests, but not on the balance beam or Rotarod.	Impairments in autophagy and lysosomal processing in neural tissues were detected in mice with germline, or adult-onset, ventral midbrain Atp13a2 KO.	Available through The Jackson Laboratory, Stock# 028387, Cryopreserved.	Kett et al., 2015	Yes
	Gba1 D409V KI Mouse (Grabowski)	<p>-</p>, <p>Gba1<sup>D409V</sup></p>, <p>9V</p>, <p>D409V</p>	Gba1^tm4Ggb	C57BL6, but may be mixed with 129Sv or FVB depending on the cross.	Gba1		This KI mouse model was generated by introducing a c.A1366T point mutation into exon 9 of the mouse Gba1 gene to create a D409V substitution in the lipid-degrading lysosomal enzyme glucocerebrosidase.	Gba1: Knock-In	Parkinson's Disease	No neurodegeneration in the hippocampus, striatum, or substantia nigra at 12 months of age. No neuroinflammation observed at 12 months of age in the hippocampus based on GFAP and Iba-1 immunostaining. Progressive α-synuclein accumulation starting as early as 4 months of age in the forebrain and hippocampus.	Memory impaired starting at 4 months in homozygous KI mice and at 9 months in D409V/null mice. Anxiety- and compulsive-like behaviors perturbed in D409V/null mice at 6 months. Gait and locomotion normal in homozygous KI mice at 8 and 12 months, but impaired gait in D409V/null mice as early as 3 months.	In 24- to 28-week-old D409V/null mice, macrophages, dendritic cells, and CD3+ T cells are increased across tissues, as are cytokine levels in serum.	N/A	Xu et al., 2003, Sardi et al., 2011	Yes
	Gba1 D409V KI Mouse (MJFF)	<p>-</p>, <p>Gba D409V KI <sup>  </sup></p>, <p>Gba<sup>tm2636(D427V)Arte</sup></p>	C57BL/6N-Gba1^tm1.1Mjff/J	Mixed C57BL/6J and C57BL/6N background.	Gba1		This constitutive KI model was generated by introducing a D427V point mutation into exon 10 of Gba1, which corresponds to the human D409V mutation (The Jackson Laboratory; Polinski et al., 2021). These mice also have loxP sites flanking exons 6 to 8, which allows for the possibility of Cre-lox-mediated recombination to knock-out the mutated gene segment selectively. This recombination deletes part of the GCase domain, resulting in a frameshift and a premature stop codon.	Gba1: Knock-In	Parkinson's Disease	No deficits in dopaminergic neuron numbers in the substantia nigra pars compacta between homozygous KI mice and wild-type mice. Dopamine levels did not differ, but dopamine turnover (ratio of DOPAC and HVA to dopamine) tended to increase at older ages. Mixed findings on GFAP and Iba-1 staining across brain regions in KI mice.	Motor function is largely intact in KI mice, apart from transient increases in locomotor activity and increased grip strength at 8 and 12 months, respectively. Cognitive performance was impaired at 12 months of age, but not at younger ages. Anxiety-like behavior was not affected.	Ocular pathology is observed in aged homozygous KI mice, including pigment dispersion, loss of iris pigmented epithelial cells, diminished iris stroma, posterior synechia, and cataracts.	Available through The Jackson Laboratory, Stock# 019106, Cryopreserved.	Polinski et al., 2021	Yes
	Gba1 L444P KI Mouse (JAX)	<p>-</p>, <p>Gba*L444P</p>, <p>Gba1<sup>tm1.1Eginn</sup></p>, <p>GbaL<sup>444P/L444P</sup></p>, <p>LP/LP</p>	B6.129X1(C)-Gba1^tm1.1Eginn/J	Mixed C57BL/6NCr and C57BL/6NJ background	Gba1		L444P KI mice were generated using a loxP replacement vector, resulting in the insertion of a point mutation of leucine to proline (L444P) in exon 10 of the Gba1 gene (Ginns et al., 2014).	Gba1: Knock-In	Parkinson's Disease	No loss of dopaminergic cells in the substantia nigra at 14 months. Inconsistent results regarding α-synuclein deposition and striatal GFAP immunostaining.	No deficits in motor balance, as detected by Rotarod and balance beam tests, observed in 16-month-old L444P KI mice.	Reduced levels of glycosylated GCase in brain lysates and reduced GCase enzyme activity in the liver, spleen, and brain. Gaucher cells may be present in the liver.	Available through The Jackson Laboratory, Stock# 024574, Cryopreserved.	Ginns et al., 2014	Yes
	Gba1 L444P KI Mouse (MMRRC)	<p>-</p>, <p>Gba<sup>L444P</sup></p>, <p>Gba<sup>L444P/L444P</sup></p>, <p>Gba<sup>+/L444P</sup></p>	B6;129S4-Gba1^tm1Rlp/Mmnc	C57BL/6 and 129S4/SvJae	Gba1		The L444P mutation was introduced into the mouse Gba gene using the single insertion mutagenesis procedure resulting in a partial duplication of the Gba locus (Liu et al., 1998).	Gba1: Knock-In	Parkinson's Disease	Dopaminergic neuron numbers are intact in the substantia nigra. Some alterations in soluble α-synuclein levels, but no findings of aggregation. Levels of dopamine and its metabolites are not perturbed in heterozygous KI mice. Neuroinflammation as measured by GFAP is not observed in heterozygous KI mice, but Iba1 staining may be increased in some regions.	Largely no differences in motor function between heterozygous KI and wild-type mice from 3 to 24 months of age. Impaired contextual, but not cued, fear conditioning at 3 months of age in heterozygous KI mice, but no deficits in olfaction or on the novel object recognition test at 24 months of age.	Homozygous KI mice are difficult to breed and require special conditions to minimize neonatal lethality. Decreased GC enzyme activity in the brain. Generally no glucosylceramide accumulation, but elevated glucosylsphingosine levels in the brain and plasma of heterozygous KI mice. Mitochondrial structure and function impaired.	Available through the Mutant Mouse Regional Resource Centres (MMRRC), Stock# 000117-UNC, Cryopreserved.	Liu et al., 1998	Yes
	HGBA L444P Tg on Gba1 KO Mouse	<p>-</p>, <p>HGBA L444P/Gba−/−</p>, <p>Tg human GCaseL444P</p>	Gba1^tm1.1Clk Tg(CAG-GBA*L483P)8Clk/Mmjax	Mixed C57BL/6, 129 Sv background.	GBA1, Gba1		The HGBA L444P/Gba−/− mouse carries a mutated human L444P HGBA transgene on a mouse Gba1 null (Gba−/−) background (Sanders et al., 2013). The mating scheme to achieve this genetic combination is to cross a haplodeficient Gba−/+ parent to a second Gba−/+ parent that additionally carries one copy of the HGBA L444P transgene.	GBA1: Transgenic; Gba1: Knock-Out	Parkinson's Disease	Older mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system glucosylsphingosine, but not glucosylceramide, were noted.	No obvious phenotypic features noted.	Lower GCase activity in the spleen, liver, and cerebrum compared to control mice. Increased levels of glucosylceramide and glucosylsphingosine in the liver and spleen. Overall health seems intact in older mice, based on the absence of splenomegaly, hepatomegaly, and hematologic abnormalities.	Available through the Mutant Mouse Regional Resource Centres (MMRRC), Stock# 050598-JAX, Cryopreserved.	Sanders et al., 2013	Yes
	HGBA N370S Tg on Gba1 KO Mouse	<p>-</p>, <p>HGBA N370S/Gba−/−</p>, <p>Tg human GCaseN370S</p>	Gba1^tm1.1Clk Tg(CAG-GBA*N409S)#Clk/Mmjax	Mixed C57BL/6, 129 Sv background.	GBA1, Gba1		The HGBA N370S/Gba−/− mouse carries a mutated human N370S HGBA transgene on a mouse Gba1 null (Gba−/−) background (Sanders et al., 2013). The mating scheme to achieve this genetic combination is to cross a haplodeficient Gba−/+ parent to a second Gba−/+ parent that additionally carries one copy of the HGBA N370S transgene.	GBA1: Transgenic; Gba1: Knock-Out	Parkinson's Disease	Older transgenic mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system glucosylsphingosine, but not in glucosylceramide, were noted.	No obvious features noted.	Drastically lower GCase activity in spleen, liver, and cerebrum compared to control mice. Increased levels of glucosylceramide and glucosylsphingosine in the liver and spleen. Overall health seems intact up to 70 weeks of age, based on the absence of splenomegaly, hepatomegaly, and hematologic abnormalities.	Available through the Mutant Mouse Regional Resource Centres (MMRRC), Stock# 050597-JAX, Cryopreserved.	Sanders et al., 2013	Yes
	LRRK2 G2019S KI Mouse		C57BL/6-Lrrk2^tm4.1Arte	C57BL/6NTac	LRRK2		Homologous recombination was used to introduce a mutation corresponding to human G2019S in exon 41 of the mouse LRRK2 gene. This KI line also has 2 loxP sites surrounding exon 41, allowing it to be crossed with a Cre line to remove the mutated exon in a spatially selective manner, although this feature has not been verified.	LRRK2: Knock-In	Parkinson's Disease	Levels of phospho-substrates of LRRK2 (e.g., Rab10) are increased in the brain. Endocytosis and axonal transport defects in neurons. Cholinergic innervation density is lower in the prelimbic/infralimbic cortical areas and dorsomedial striatum, but not in the dorsal lateral geniculate nucleus in 2-6-month-old males. Microglial immunostaining is similar in the striatum and midbrain at 8 weeks	Attention deficits, slower information processing speeds, and impaired goal-directed learning are evident in 2-6-month-old mice—deficits rescued by systemic administration of the acetylcholinesterase inhibitor donepezil. Cognitive flexibility and novel objective recognition similar to controls. Sleep behavior is perturbed at 8-10 months of age.	Functional and structural synaptic alterations and impaired synaptic plasticity observed during development (P21) in the dorsal striatum and NAc, some of which may be transient. Impaired synaptic plasticity (LTP) in striatum present early (P21) and persists into adulthood.	Available through Taconic, Cat#13940, Live. Research services with this model are available from Scantox Neuro.	Matikainen-Ankney et al., 2016	Yes
	LRRK2 G2019S Mouse (BAC Tg)	<p>-</p>, <p>BAC Lrrk2-G2019S</p>, <p>FLAG-Lrrk2-G2019S</p>, <p>BAC-Lrrk2-G2019S</p>, <p>LRRK2 G2019S BAC Tg Mouse (Yue)</p>	B6.Cg-Tg(Lrrk2*G2019S)2Yue/J	A BAC construct was injected into B6C3 F1 oocytes. Founder line 2 was established and maintained by breeding to C57BL/6J inbred mice.	LRRK2	LRRK2 G2019S	A bacterial artificial chromosome (BAC) containing the entire mouse Lrrk2 gene was modified to include the G2019S mutation. The BAC (~240 kb) contained the murine Lrrk2 promoter region (~35 kb) and a FLAG-tag downstream of the start codon.	LRRK2: Transgenic	Parkinson's Disease	Brain appears normal. No neuronal or cell death at 12 months. Impaired neurite motility and synaptic vesicle endocytosis in cultured neurons. No increase in α-synuclein or ubiquitin levels or aggregation; however, cultured neurons developed more inclusions when exposed to exogenous α-synuclein fibrils. Decreased striatal dopamine content, decreased evoked release.	Apparently normal behavior. No change in activity level or motor coordination at 12 months. Motor deficits appear at 18 months.	Mutant Lrrk2 protein purified from mouse brain had increased kinase activity. Age-dependent electrophysiological changes in the hippocampus including increased basal synaptic efficiency though a postsynaptic mechanism and decreased LTD. Synaptic vesicle endocytosis impaired in cultured ventral midbrain neurons. Tg mice spend less time in the REM sleep phase.	Available through The Jackson Lab, Stock# 012467, cryopreserved.	Li et al., 2010	Yes
	LRRK2 G2019S Mouse (Tg)	<p>-</p>, <p>G2019S-LRRK2 (line 340)</p>, <p>G2019S-LRRK2 transgenic</p>, <p>LRRK2 G2019S Tg Mouse (Dawson/Moore)</p>	B6;C3-Tg(PDGFB-LRRK2*G2019S)340Djmo/J	Transgene introduced into C57BL/6J x C3H/HeJ embryos. Founder mice were bred with C57BL/6J mice.	LRRK2	LRRK2 G2019S	Transgenic mice overexpress full-length mutant human LRRK2 with the G2019S mutation. Transgene expression is driven by a hybrid CMVe-PDGFβ promoter.	LRRK2: Transgenic	Parkinson's Disease	Age-dependent dopaminergic neuron degeneration in the substantia nigra, though reports are mixed. No reduction in striatal dopaminergic terminals or dopamine levels. Some reports of α-synuclein accumulation. Abnormal mitochondria in striatal neurons and microglia; accumulation of autophagic vacuoles. Evidence for activated striatal microglia and increased levels of CD68 and TNF-α in whole brain.	Deterioration of Rotarod performance in 14- to 18-month-old mice. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex. Anxiety/depression-like symptoms at 10-12 months.	No differences in body weight or survival. Reduced serotonin levels in the hippocampus at 10-12 months. Age-dependent increase in 5-HT1a receptors in the hippocampus, amygdala, and dorsal raphe nucleus.	Available through The Jackson Laboratory, Stock# 016575, Cryopreserved.	Ramonet et al., 2011	Yes
	Lrrk2 KO Mouse	<p>-</p>, <p>Lrrk2 knockout mouse</p>, <p>LRRK2−/−</p>	B6.129X1(FVB)-Lrrk2^tm1.1Cai/J	C57BL/6J (but may be mixed with C57BL/6N)	Lrrk2		Lrrk2 KO mice were generated by Cre-mediated deletion of coding exon 2 of the Lrrk2 gene, which results in a premature stop codon in exon 3 (Lin et al., 2009). Heterozygous KO mice were intercrossed to generate homozygous KO mice (Parisiadou et al., 2009).	Lrrk2: Knock-Out	Parkinson's Disease	No loss in the number of TH–positive cells in the substantia nigra pars compacta up to 24 months. Cerebral cortex and dorsal striatum volumes reduced at 12 months. Striatal spiny projection neurons were enlarged and the frequency of nuclear invaginations was increased at 12 months, suggesting premature aging. Dendritic morphology perturbed at 12 months.	No differences between KO and wild-type mice up to 24 months on several behavioral tests, including the elevated plus maze for anxiety-like behavior, the buried treat test to measure hyposmia, the grip strength test for forelimb strength, or working memory as measured by spontaneous alternation. Older (24-month-old) mice showed deficits in motor skill learning as measured by Rotarod.	Lysosomal dysregulation is observed in the striatum and kidneys of KO mice. Immune responses perturbed upon challenge with a pathogen.	Available through The Jackson Laboratory, Stock# 012453, Cryopreserved or frozen embryo.	Parisiadou et al., 2009	Yes
	LRRK2 R1441C KI Mouse	<p>-</p>, <p>LRRK2 R1441C knock-in</p>, <p>R1441C KI</p>, <p>RC KI</p>, <p>Lrrk2 R1441C-KI</p>	B6.Cg-Lrrk2^tm1.1Shn/J	The mutant colony was established in B6/129 F1 mice, but backcrossed to C57BL/6J wild-type mice for at least 12 generations.	LRRK2		The KI mouse model was generated by homologous recombination in (C57BL/6×129)F1-derived embryonic stem cells. A 1.7-kb DNA fragment containing the R1441C missense mutation was electroporated using site-directed mutagenesis into the GTPase domain of exon 31 of the Lrrk2 locus. The colony was established in B6/129 mice, but backcrossed to C57BL/6J wild-type mice for at least 12 generations.	LRRK2: Knock-In	Parkinson's Disease	No loss of dopaminergic (TH+) neurons in the substantia nigra pars compacta at 12 and 22 months. No loss of TH-immunoreactive neurons in the locus coeruleus. Basal levels of striatal dopamine, DOPAC, and HVA were comparable between KI and wild-type mice at 3, 12, and 23 months. However, evoked dopamine release in the striatum was reduced in adult heterozygous KI mice.	Acoustic startle reflex equal to wild-type mice at 12 months of age. Motor learning impaired upon antagonism of dopamine receptors (D1 and D2).	Intracellular protein transport impaired. PKA activity is elevated in the striatum. Ciliation in striatal cholinergic neurons is decreased and primary cilia formation is perturbed in the somatosensory cortex.	Available through The Jackson Laboratory, Stock# 009346, Cryopreserved or frozen embryo.	Tong et al., 2009	Yes
	LRRK2 R1441C Mouse (Tg - Conditional)	<p>-</p>, <p>R26-LRRK2; R26-LRRK2<sup>+/+</sup></p>, <p>R26-LRRK2<sup>+/+</sup>/DAT-Cre mice</p>, <p>ROSA26-LRRK2(R1441C)</p>, <p>R1441C LRRK2 Tg Mouse (Moore)</p>	STOCK Gt(ROSA)26Sortm1(LRRK2*R1441C)Djmo/J	R26-LRRK2 mice were generated from 129/SvJ ES cells microinjected into C57Bl/6J mouse blastocysts. Chimeras were bred with C57Bl/6J mice and maintained on a mixed genetic background (129/SvJ and C57Bl/6J). BAC-DAT-iCRE mice were maintained on a C57Bl/6J background.	LRRK2	LRRK2 R1441C	Full-length human LRRK2 with the R1441C mutation was targeted to the endogenous ROSA26 locus by homologous recombination. Cre-mediated excision of the transcriptional termination sequence allows for transgene expression. The Cre line expressed Cre-recombinase driven by the dopamine transporter (DAT) promoter derived from a BAC construct containing the entire mouse DAT (slc6) gene.	LRRK2: Transgenic	Parkinson's Disease	No neurodegeneration in the brain. No proteinaceous inclusions of α-synuclein, ubiquitin, or tau. No reactive gliosis. No change in dopamine levels. Subtle morphological abnormalities in dopaminergic and non-dopaminergic neuronal nuclei, including altered nuclear envelope.	No overt behavioral differences. Activity levels and Rotarod performance are normal into advanced age.	Fertile. Normal survival. No overt olfactory deficits.	Available through The Jackson Laboratory, Stock# 022793, Cryopreserved or frozen embryo.	Tsika et al., 2014	Yes
	LRRK2 WT Mouse (BAC Tg)	<p>-</p>, <p>WT-OX</p>, <p>LRRK2 WT BAC</p>, <p>WT LRRK2 Mouse (BAC Tg)</p>, <p>WT LRRK2 BAC Tg Mouse (Li)</p>	FVB/N-Tg(LRRK2)1Cjli/J	BAC injected into fertilized FVB zygotes. Founder mice bred with FVB/N inbred mice for many generations, and then with FVB/NJ inbred mice.	LRRK2		A 188 kb human bacterial artificial chromosome (BAC) containing the entire human LRRK2 gene, with 29 kb upstream and 42 kb downstream.	LRRK2: Transgenic	Parkinson's Disease	Overtly normal brain structure. Intact, but shorter, neurites.	Motor hyperactivity at 12 months of age.		Available through The Jackson Laboratory, Stock# 009610, Cryopreserved.	Li et al., 2009	Yes
	MCI-Park Mouse	<p>-</p>	Ndufs2^tm1.1Job Slc6a3^{tm1.1(cre)Bkmn}/SurmJ	Mixed 129, C57BL/6J, C57BL/6N, and SJL background.			Ndufs2fl/fl mice contain two loxP sites flanking exon 2 of the Ndufs2 gene, and DATIREScre/+ mice contain an internal ribosome entry site–linked Cre recombinase downstream (23 bp) from the stop codon of the endogenous Slc6a3 gene (The Jackson Laboratory).	Conditional Knock-out	Parkinson's Disease	Progressive reductions in TH expression in the striatum and SN. Overt neuron loss in the SN only at older ages (>120 days). Electrophysiological measurement of SN dopaminergic neurons showed altered pacemaking activity and burst spiking. Altered expression of many neuronal genes. Loss of evoked dopamine release in the dorsolateral striatum at 30 days of age.	Impaired associative learning and striatal motor learning at 30 days. Impaired rearing at 40 days. Decreased total distance travelled by 60 days. By 100 days, splayed hindlimbs, abnormal paw placement, and alterations in stride. Impaired sleep functions starting at 6 weeks.	Metabolic reprogramming to a glycolytic-predominant state of mitochondria. By 20 days, mitochondria were in an oxidative phosphorylation deficit. Altered mitochondria structure, but not mitochondrial density, observed at 35 days in dopaminergic neurons of the SN.	Available through The Jackson Laboratory, Stock# 036313, Live and cryopreserved.	González-Rodríguez et al., 2021	Yes
	Parkin Q311X Mouse (BAC Tg)	<p>-</p>, <p>PARK2-Q311X</p>, <p>Parkin-Q311X(A)</p>, <p>Parkin-Q311X (line A)</p>, <p>Parkin Q311X BAC Tg Mouse (Yang)</p>, <p>Parkin Q311(X)A</p>	FVB/NJ-Tg(Slc6a3-PARK2*Q311X)AXwy/J	The BAC was microinjected into fertilized FVB/NJ zygotes, then bred to FVB/NJ inbred mice.	Park2	Parkin Q311X	Parkin-Q311X mice have bacterial artificial chromosome (BAC)-mediated expression of mutant parkin in dopaminergic neurons. The promoter and regulatory regions of the Slc6a3 gene (encoding a dopamine transporter) drive expression of parkin with the truncation mutation Q311X. The protein has an N-terminal FLAG-tag. Two copies of the transgene are integrated in tandem.	Park2: Transgenic	Parkinson's Disease	Degeneration of dopaminergic neurons in the SN and nerve terminals in the striatum. Reduced dopamine in the striatum. Accumulation of proteinase-K resistant α-synuclein and oxidative protein damage. Dysfunction in the burst-firing pattern activity of dopaminergic SN neurons and increased expression of markers for excitotoxic damage.	Late-onset hypoactivity (about 16 months of age), other modest changes in motor behavior and coordination in tests that included traversing a beam or removing adhesive.	Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.	Available through The Jackson Laboratory, Stock# 009090, cryopreserved or frozen embryo.	Lu et al., 2009	Yes
	Parkin S65A KI Mouse	<p>-</p>, <p>Parkin S65A KI</p>, <p>Parkin<sup>S65A/S65A</sup></p>	C57BL/6-Prkn^tm1.1Muqit/J	C57BL/6J	Park2	Park2 S65A	This constitutive KI mouse model was generated by Flp-mediated homologous recombination in mouse embryonic stem cells to introduce an S65A point mutation in exon 3 of the Park2 (Parkin) gene (McWilliams et al., 2018).	Park2: Knock-In	Parkinson's Disease	No evidence of nigrostriatal neuropathology in 18-month-old homozygous mice.	Motor dysfunction on the raised balance beam by 12 months of age. No deficits in Rotarod performance or gait.	Impairments in mitochondrial respiration, but not basal mitophagy, in an age-dependent manner.	Available through The Jackson Laboratory, Stock# 029247, Cryopreserved.	McWilliams et al., 2018	Yes
	PINK1 G309D (PINK1-/-) Mouse (KI)	<p>-</p>, <p>Pink1<sup>-/-</sup></p>, <p>Pink1<sup>-</sup></p>, <p>Pink1-deficient mouse</p>, <p>PARK6 mouse</p>, <p>PINK1 G309D (PINK1-) KI Mouse (Auburger)</p>, <p>Pink1*G308D</p>, <p>PINK1-knockout</p>	B6;129-Pink1^tm1Aub/J	The vector was introduced into a 129/SvEV-derived embryonic stem cell line. Resulting chimeric mice were bred and maintained on a pure 129 background.	PINK1	Pink1 G309D	A targeting vector was used to introduce the G309D mutation into exon 4 at the orthologous mouse locus. A floxed neomycin cassette in the inverse orientation was inserted into intron 5 via homologous recombination.	PINK1: Knock-In	Parkinson's Disease	No neuronal loss. No Lewy bodies or α-synuclein aggregates, but α-synuclein expression change in brainstem/midbrain. Low dopamine levels. Mitochondrial dysfunction (e.g., reduced ATP, reduced respiratory activity). Increase in factors involved in Toll-like receptor signaling in the cerebellum, and increased astrocytic and microglial markers in the corticospinal tract and striatum.	Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination.	Electrophysiological abnormalities, including altered glutamergic activity in midbrain dopaminergic neurons and early hypersynchrony in motor cortex. Medium spiny neurons in striatal slice exhibit giant GABAergic currents. Hyperactive subthalamic nucleus neurons, indicated by spontaneous bursts instead of single spikes. Subtle alterations in gene expression in cerebellum, midbrain, and striatum.	Available through The Jackson Laboratory, Stock# 013050, Cryopreserved.	Gispert et al., 2009	Yes
	PINK1 KO Mouse	<p>-</p>, <p>Pink1 KO</p>, <p>Pink1 knockout mouse</p>, <p>Pink1-</p>, <p>Pink1<sup>-/-</sup></p>, <p>PINK1 KO Mouse (Shen)</p>	B6.129S4-Pink1^tm1Shn/J	Congenic C57BL/6J. The construct was introduced into 129S4/SvJae-derived J1 embryonic stem cells, which were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to generate homozygotes and then backcrossed to C57BL/6J for >7 generations.	Pink1		A targeting vector containing a PGK-Neo cassette was used to disrupt exons 4 through 7 of the endogenous PINK1 gene. This creates a nonsense mutation at the beginning of exon 8; truncated RNA is degraded.	Pink1: Knock-Out	Parkinson's Disease	Normal numbers of dopaminergic neurons and tyrosine hydroxylase levels in substantia nigra at 8-9 months of age. Alterations in the dendrites of midbrain dopaminergic neurons and cultured cortical neurons. Altered shape, density, and movement of dendritic mitochondria in cultured primary neurons from embryonic mice. Reduced BDNF levels in the midbrain and cortex at 10 months.	Reduced spontaneous locomotor activity and skill at 3-6 months. Modest vocalization deficits at 4-6 months.	Heavier than wildtype mice at 5 months. Plasticity abnormalities: reduced LTP and absent LTD in response to high frequency stimulation; reversed by dopamine agonists. Abnormal rise in serum cytokines in response to exhaustive exercise which acutely stresses mitochondria. Cardiac hypertrophy observed at 2 and 6 months of age.	Available through The Jackson Laboratory, Stock# 017946; Live.	Kitada et al., 2007	Yes
	α-synuclein A30P/A53T Mouse (Tg)	<p>-</p>, <p>hm<sup>2</sup>α-SYN-39</p>, <p>HM2</p>, <p>hm<sup>2</sup>α-SYN, human doubly mutated α-synuclein</p>, <p>A30P/A53T aSyn Mouse (Tg)</p>, <p>A30P/A53T aSyn Tg Mouse (Richfield)</p>, <p>alpha-synuclein A30P/A53T Mouse (Tg)</p>, <p>B6J(<sup>2</sup>39)</p>	C57BL/6J-Tg(Th-SNCAA30PA53T)39Eric/J	Transgene injected into C57/BL6 oocytes, then bred to C57/BL6J.	SNCA	SNCA A30P, SNCA A53T	This model expresses a transgene encoding human α-synuclein with two mutations (A30P and A53T) driven by 9kb rat tyrosine hydroxylase (TH) promoter.	SNCA: Transgenic	Parkinson's Disease	Progressively loss of dopaminergic neurons in the substantia nigra pars compacta, observed by 8.5 months. No α-synuclein inclusions. Morphological abnormalities in the dopaminergic system, including axonal and dendritic abnormalities, reduced dopamine concentration in the striatum.	More active as young adults, then hypoactive compared to non-Tg. Also reduced motor coordination in old age as measured by the time to right from an inverted wire screen.	No weight differences compared to non-Tg.	Available through The Jackson Laboratory, Stock# 008239, Live.	Richfield et al., 2002	Yes
	α-synuclein A53T Mouse (Tg)	<p>-</p>, <p>G2-3(A53T)</p>, <p>PrPsynA53T</p>, <p>A53TαS Tg mice (line G2-3)</p>, <p>MoPrP-Huα-Syn(A53T)</p>, <p>Hualpha-Syn(A53T)</p>, <p>A53T aSyn Tg Mouse (Lee)</p>, <p>alpha-synuclein A53T Mouse (Tg)</p>	B6.Cg-2310039L15Rik^{Tg(Prnp-SNCAA53T)23Mkle}/J. Formerly: B6.Cg-Tg(Prnp-SNCAA53T)23Mkle/J	Established as C3H/HeJ x C57BL6/J hybrids, then maintained by backcrossing to C57Bl6/J.	SNCA	SNCA A53T	Transgene comprising human α-synuclein with the A53T mutation was inserted downstream of the mouse prion protein (PrP) promoter.	SNCA: Transgenic	Parkinson's Disease	No overt neuronal loss. Alterations in dopaminergic-associated proteins in the striatum, substantia nigra, and nucleus accumbens. Region-specific neuronal accumulation of fibrillar α-synuclein, ubiquitin, and neurofilament-H, and accompanying astrocytosis.	Early hyperactivity followed by severe motor impairment, manifesting as wobbling, posturing, decreased spontaneous locomotor behavior, inability to navigate the Rotarod, and ultimately paralysis and death. At 11–12 months, spatial memory impaired as assessed by the Barnes circular maze.	Premature death, defects in hippocampal synaptic function.	Available through The Jackson Laboratory, Stock# 006823, Live.	Lee et al., 2002	Yes
	α-synuclein A53T Mouse (Tg) on SNCA KO	<p>-</p>, <p>PAC-Tg(SNCA-A53T) <sup>+/+</sup>; Snca<sup>-/-</sup></p>, <p>dbl-PAC-Tg(SNCA<sup>A53T</sup>);Snca<sup>-/-</sup></p>, <p>A53T aSyn Tg Mouse (Nussbaum)</p>, <p>Alpha-synuclein A53T Mouse (Tg) on SNCA KO</p>	FVB;129S6-Snca^tm1Nbm Tg(SNCAA53T)1Nbm Tg(SNCAA53T)2Nbm/J	The PAC transgene was injected into FVB/N oocytes and founder mice bred to FVB/N. The knockout mice were made in a 129S6/SvEvTac background.	SNCA	SNCA A53T	In this double-transgenic model, one parental line expresses mutant human α-synuclein (A53T mutation) via a 146 kb P1 artificial chromosome (PAC) containing full-length human SNCA gene and 34 kb upstream sequence. The other line is an Snca knockout line generated by replacing exons 4 and 5 with a neomycin resistance cassette.	SNCA: Transgenic; SNCA: Knock-Out	Parkinson's Disease	No loss of dopaminergic neurons in the substantia nigra by 18 months of age. Rare dystrophic synapses in the hippocampus at advanced age, but no Lewy body-like pathology or α-synuclein aggregation in the brain. No change in striatal dopamine concentration.	Impaired performance on the Rotarod and reduced spontaneous locomotor activity in open-field test.	Gastrointestinal dysfunction (e.g., reduced fecal mass, reduced colonic motility, prolonged whole-gut transit time). α-synuclein–positive aggregates in enteric nervous system. No difference in body weight. No olfactory deficits. No difference in autonomic regulation of heart rate.	Available through The Jackson Laboratory, Stock #010799; Live.	Kuo et al., 2010, Cabin et al., 2002	Yes
	α-synuclein KO Mouse	<p>-</p>, <p>Snca KO</p>, <p>Snca -/-</p>, <p>Snca KO Mouse (Nussbaum)</p>, <p>Alpha-synuclein KO Mouse</p>		Inbred 129/SvEvTac background.	SNCA		The mouse Snca gene was disrupted using a targeting vector that replaced exons 4 and 5 with the neomycin resistance gene.	SNCA: Knock-Out	Parkinson's Disease	No gross brain abnormalities. Electron microscopy revealed synaptic vesicle abnormalities in hippocampal neurons, i.e., fewer vesicles in the reserve pool.	Behavior is largely normal. Normal performance on the Rotarod. Subtle differences in locomotor activity (e.g., less rearing) but normal overall distance travelled. Learning and memory appear intact. Possible anxiety-like phenotype.	Microglial abnormalities. Reduced cardiolipin content in the brain. Some mitochondrial abnormalities.	Unknown.	Cabin et al., 2002	Yes
	α-synuclein KO Mouse (Conditional)	<p>-</p>, <p>Sncaflox(neo)</p>, <p>SNCAflox delta neo</p>, <p>Snca conditional knockout</p>, <p>SNCA KO Mouse (Buchman)</p>, <p>Alpha-synuclein KO Mouse (Conditional)</p>	B6(Cg)-Snca^tm1.1Vlb/J	C57BL/6J	SNCA		A targeting vector containing a FRT site-flanked neomysin cassette and a loxP site was inserted downstream of exon 2 and another loxP site was inserted upstream of exon 2. Flp-mediated recombination removed the FRT-flanked neo cassette, leaving exon 2 floxed. When bred to Cre-expressing mice, the resulting offspring have the first coding exon deleted in Cre-expressing tissues.	SNCA: Conditional Knock-out	Parkinson's Disease	No data.	No data.		Available through The Jackson Laboratory, Stock #025636, Live.	Ninkina et al., 2015, Roman et al., 2017	Yes
	Thy1-αSyn “Line 61” Mouse	<p>-</p>, <p>mThy1-α-synuclein</p>, <p>mThy-1 tg</p>, <p>Tg(Thy1-SNCA)61Ema</p>	B6;DBA-Tg(Thy1-SNCA)61Ema	(C57BL/6 x DBA/2)F1 (strain of origin)	SNCA		This transgenic mouse expresses human wild-type α-synuclein under the control of the mouse Thy1 promoter (Rockenstein et al., 2002). The transgene is inserted in the X chromosome.	SNCA: Transgenic	Parkinson's Disease				Available through Eliezer Masliah, Robert Rissman for academic research; others please contact the Office of Innovation and Commercialization at the University of California, San Diego. The CRO Scantox Neuro offers research services with this model.	Rockenstein et al., 2002	Yes
	Vps35 p.D620N KI Mouse	<p>-</p>	B6.Cg-Vps35^tm1.1Mjff/J	C57BL/6J	Vps35		This constitutive KI mouse model expresses the g.85,263,520G>A missense mutation in exon 15 of Vps35, which leads to the mutated (D620N) protein (Cataldi et al., 2018). The model was generated to drive mutant protein expression at physiological levels and avoid the confounds of random insertion. This KI model was created and maintained in C57Bl/6J mice (The Jackson Laboratory).	Vps35: Knock-In	Parkinson's Disease	Loss of TH+ neurons in SNpc and TH+ terminals in striatum at 13-16 mos. Widespread axonal degeneration at 13 mos. Increased somatic α-synuclein in SNpc; α-synuclein oligomers and aggregates in ventral midbrain at 15-16 mos. Increased somatodendritic tau/p-tau with age, but no neurofibrillary pathology. Increased GFAP in SNpc, but not striatum at 15-16 mos. No microgliosis up to 16 mos.	No deficits in the buried pellet test, measuring olfactory function, from 6-14 months. Deficits in mood (anxiety/apathy) and/or cognition on elevated plus maze, starting at 3 months (unpublished).	No defects in gastrointestinal function up to 14 months of age.	Available through The Jackson Laboratory, Stock# 023409, Cryopreserved.	Cataldi et al., 2018, Chen et al., 2019, Niu et al., 2021	Yes
Rat Models (6)
	DJ-1 KO Rat	<p>-</p>, <p>DJ-1 knockout rat</p>	LE-Park7^em1sage; HsdSage:LE-Park7^em1Sage; formerly LEH-Park7^tm1sage	Long Evans Hooded	Park7 (DJ1)		Disruption of the DJ-1 gene by zinc finger nuclease (ZFN) technology. ZFNs were engineered to bind to a recognition sequence in exon 5 of PARK7 and cleave DNA.	Park7 (DJ1): Knock-Out	Parkinson's Disease	Age-related decrease in dopaminergic neurons in the substantia nigra and locus coeruleus; approximately 50 percent reduction by 8 months. Striatal dopamine and serotonin levels elevated 2-3fold over wild-type levels. No change was found in TH-immunoreactivity in the ventral tegmental area or striatum.	Enhanced olfactory detection, abnormal short-term memory, impaired coping behavior, reduced anxiety on light-dark box. Abnormalities in gait, paw positioning, strength, vocalizations, and tongue movements. In males, impaired licking, longer and more frequent ultrasonic vocalizations, and accelerated decrease in average call intensity with age.	No increase in mortality up to 8 months of age.	Available through I notiv. Cryopreserved. (Previously available through Horizon Discovery (formerly Sage Labs), Cat #TGRL4830)	Dave et al., 2014	Yes
	LRRK2 G2019S Rat (BAC Tg)	<p>-</p>, <p>Line 10681</p>, <p>hBAC G2019S-LRRK2</p>, <p>LRRK2 G2019S rat</p>	NTac:SD-Tg(LRRK2*G2019S)571CJLi	Sprague-Dawley	LRRK2	LRRK2 G2019S	BAC construct carrying the human gene Lrrk2 with the G2019S mutation.	LRRK2: Transgenic	Parkinson's Disease	No overt neurodegeneration out to 12 months of age. Elongated dopaminergic neurons. Elevated oxidative and nitrosative stress. No evidence of gliosis. No α-synuclein inclusions until challenged with exogenous α-synuclein. No change in dopamine levels.	Mild abnormalities in motor behavior. Slightly more postural instability at 8 months of age (but not at 4 and 12 months). Slightly more rearing events at 12 months, but not at younger ages.	Bone marrow myeloid progenitor numbers were decreased, but suppressive myeloid cells were increased at 6 to 11 months of age.	Available through Taconic, Cat# 10681, Cryopreserved. Research services with this model are available from Scantox Neuro.	West et al., 2014	Yes
	Lrrk2 KO Rat	<p>-</p>, <p>Lrrk2 knockout rat</p>	LEH-Lrrk2^tm1sage, HsdSage: LE-Lrrk^tm1sage, formerly known as TGRL4620	Long Evans Hooded	Lrrk2		Zinc finger nuclease (ZFN) technology was used to generate a deletion of 10 base pairs in exon 30 of the rat Lrrk2 gene. This resulted in a frameshift and a premature stop codon in the same exon.	Lrrk2: Knock-Out	Parkinson's Disease	Not observed. Protection against dopaminergic cell loss under conditions involving LPS or α-synuclein overexpression in the substantia nigra. No changes in basal or evoked release of dopamine.	One assessment of Rotarod performance revealed no impairment at 12 months of age compared with wild-type rats.	Abnormalities in peripheral organs, including the kidney, liver, and lung. Lifespan and organ function are not adversely affected by Lrrk2 knockout.	Available through I notiv, Live and cryopreserved.	Baptista et al., 2013, Ness et al., 2013	Yes
	Parkin KO Rat	<p>-</p>, <p>Park2 KO</p>, <p>Parkin knockout rat</p>	HsdSage:LE-Park2^em1Sage; formerly LEH-Park2^TM1sage	Long Evans Hooded	Park2		The rat Park2 gene was disrupted using zinc finger nuclease (ZFN) technology, in which targeted ZFN RNA was injected into fertilized eggs. The ZFNs were engineered to bind to a recognition site sequence in exon 4 of Park2 and cleave the DNA. When the resulting double strand break was repaired by non-homologous end joining, a deletion of five base pairs was created in the founder rat. This deletion led to a frame shift and the creation of a premature stop codon.	Park2: Knock-Out	Parkinson's Disease	No significant changes in dopaminergic neurons in the substantia nigra nor striatal dopamine levels, but alterations in dopaminergic signaling were detected at an early age, as were disruptions in mitochondrial protein expression in striatum. No increase in α-synuclein. Evoked release of striatal glycine greater at 12 months versus wild-type rats.	No behavioral deficits detected at 4, 6, and 8 months of age. However, at 2 months, male KO rats made fewer small stereotypic movements, such as scratching and grooming, than wild-type controls. At 2 months, male KO rats had a greater preference for methamphetamine than wild-type rats.		Available through I notiv. Cryopreserved as heterozygous embryos. (Previously available through Envigo).	Dave et al., 2014	Yes
	Pink1 KO Rat	<p>-</p>, <p>Pink1 knockout rat</p>, <p>Park6 KO rat</p>	HsdSage:LE-Pink1^em1Sage; formerly LEH-Pink1^tm1Sage-/-	Long Evans Hooded	Pink1		The rat Pink1 gene was disrupted using zinc finger nuclease (ZFN) technology. The ZFNs were engineered to bind to a recognition site in exon 4 of Pink1 and cleave the DNA. When the resulting double strand break was repaired, a deletion of 26 base pairs was created. This deletion lead to a frameshift and the creation of a premature stop codon.	Pink1: Knock-Out	Parkinson's Disease	Age-related decrease in dopaminergic neurons in the substantia nigra; greater than 50 percent reduction at eight months. Alterations in striatal dopamine and serotonin levels. Progressive increase in α-synuclein aggregates and reduced brain volume across numerous regions. Increased ventricular volume. Alterations in cortical and striatal mitochondria.	Abnormalities in gait, coordination, and strength. As early as 5 weeks of age, KOs had increased foot slips on the tapered balance beam, at 7 weeks they showed hind limb fatigue, which progressed to hind limb dragging, and by 2 months they exhibited alterations in oromotor (lingual) behaviors.	Heavier than wild-type rats at 4, 6, and 8 months of age. No increase in mortality. Early (3 months of age) gene expression changes in whole blood, indicative of inflammation-related changes. Gastrointestinal dysfunction appears within 6 months of age.	Available through I notiv. Live. (Previously available through Envigo (formerly Horizon Discovery and Sage Labs), Cat# TGRL4690)	Dave et al., 2014	Yes
	α-synuclein E46K Rat (BAC Tg)	<p>-</p>, <p>α-synuclein (E46K) rat, founder line 70</p>, <p>Human α-synuclein E46K rat</p>, <p>E46K aSyn Rat</p>, <p>Alpha-synuclein E46K Rat (BAC Tg)</p>	NTac:SD-Tg(SNCA*E46K)70CJLi	Sprague-Dawley	SNCA	SNCA E46K	A bacterial artificial chromosome (BAC) was used to introduce human α-synuclein with the E46K mutation.	SNCA: Transgenic	Parkinson's Disease	No overt neuronal loss. Accumulation of mutant α-synuclein in the brain, in the form of diffuse staining and intracellular aggregates. Aggregates were largely restricted to dopaminergic neurons of the substantia nigra and ventral tegmental area. Elevated nitrotyrosine in dopaminergic neurons.	No overt behavioral changes until challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity.	Viable and fertile.	Available through Taconic Cat #10679; Cryopreserved.	Cannon et al., 2013	Yes

32 Visualizations

Phenotypes Examined

Neuronal Loss
Dopamine Deficiency
α-synuclein Inclusions
Neuroinflammation
Mitochondrial Abnormalities
Motor Impairment
Non-Motor Impairment

When visualized, these phenotypes will distributed over a 18 month timeline demarcated at the following intervals: 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.

Atp13a2-flox Mouse

Observed

X
Neuroinflammation at 4

Germline Atp13a2 KO mice exhibit progressively worsening astrogliosis starting as early as 1 month of age, but in mice with adult-onset Atp13a2 KO in the ventral midbrain, astrogliosis and microglial reactivity were present only transiently after AAV-Cre delivery.
X
Motor Impairment at 39

Germline Atp13a2 null mice exhibit some motor defects on the open-field test (starting at 9 months of age) and in the tail suspension test (at 18 months of age), but other motor measures (including balance beam and Rotarod performance) did not differ from wild-type mice.
X
Neuronal Loss at 52

No cell loss in the substantia nigra pars compacta (SNpc) in germline Atp13a2 null mice by 18 months of age, but in mice with adult-onset Atp13a2 KO in the ventral midbrain (via AAV-Cre delivery), dopaminergic neuronal degeneration in the SN was observed 10 months after injection (i.e., in 12- to 16-month-old mice).

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Atp13a2		Atp13a2: Knock-Out	Parkinson's Disease	Adult-onset Atp13a2 KO in the ventral midbrain (via AAV-Cre delivery) resulted in neuropathology, including dopaminergic neuronal degeneration in the SN, which was not observed in germline Atp13a2 KO mice.	Motor function partially impaired in germline Atp13a2 KO mice, including defects on the open-field and tail suspension tests, but not on the balance beam or Rotarod.

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DJ-1 KO Rat

Observed

X
Non-Motor Impairment at 17

Olfactory detection enhanced (16 mos). Short-term memory abnormal (4.5, 15 mos). Appetitive instrumental learning normal (4, 6, 8 mos). Coping behavior (forced-swim test) impaired (6 mos). No anxiety-like behavior (elevated plus maze; 4, 8, 17 mos), less anxiety on light-dark box (6, 8 mos). No sucrose preference at 9 mos. Sensorimotor function (adhesive removal) unaffected (4, 7, 13 mos).
X
Motor Impairment at 17

Abnormalities in gait and strength, vocalizations, and tongue movements were observed. By 4 months, the rats exhibited abnormal paw positioning and a shorter stride. Males showed impaired licking, longer and more frequent ultrasonic vocalizations, and an accelerated decrease in average call intensity with age. Fine motor skills were also impaired in KO versus wild-type rats by 7 months of age.
X
Mitochondrial Abnormalities at 13

At 3 months of age, the mitochondrial proteome in DJ-1 KO rats was differentially expressed compared to wild-type rats. Mitochondrial respiration was also increased in KO versus wild-type rats
X
Neuronal Loss at 26

Age-related decreases in TH-positive dopaminergic neurons were reported in the substantia nigra and locus coeruleus reaching approximately 50 percent by 8 months of age. No change was found in TH-immunoreactivity in the ventral tegmental area or striatum.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Park7 (DJ1)		Park7 (DJ1): Knock-Out	Parkinson's Disease	Age-related decrease in dopaminergic neurons in the substantia nigra and locus coeruleus; approximately 50 percent reduction by 8 months. Striatal dopamine and serotonin levels elevated 2-3fold over wild-type levels. No change was found in TH-immunoreactivity in the ventral tegmental area or striatum.	Enhanced olfactory detection, abnormal short-term memory, impaired coping behavior, reduced anxiety on light-dark box. Abnormalities in gait, paw positioning, strength, vocalizations, and tongue movements. In males, impaired licking, longer and more frequent ultrasonic vocalizations, and accelerated decrease in average call intensity with age.

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Gba1 D409V KI Mouse (Grabowski)

Observed

X
Non-Motor Impairment at 17

Memory is impaired starting at 4 months in homozygous KI mice based on the novel object recognition and contextual fear-conditioning tests. In D409V/null mice, memory was impaired at 9 months; heterozygous KI mice did not exhibit memory deficits at 6 months. Anxiety- and compulsive-like behaviors were perturbed in D409V/null mice at 6 months, based on the marble burying test.
X
α-synuclein Inclusions at 18

Progressive α-synuclein accumulation starting at 6 months of age in homozygous and heterozygous KI mice as well as in D409V/null mice, and may be present even as early as 4 months of age, in the forebrain and hippocampus.
X
Motor Impairment at 14

Homozygous KI mice do not exhibit gait abnormalities or locomotion based on the open-field test, at 8 and 12 months, respectively. However, D409V/null mice exhibit perturbances in gait as early as 3 months of age.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Gba1		Gba1: Knock-In	Parkinson's Disease	No neurodegeneration in the hippocampus, striatum, or substantia nigra at 12 months of age. No neuroinflammation observed at 12 months of age in the hippocampus based on GFAP and Iba-1 immunostaining. Progressive α-synuclein accumulation starting as early as 4 months of age in the forebrain and hippocampus.	Memory impaired starting at 4 months in homozygous KI mice and at 9 months in D409V/null mice. Anxiety- and compulsive-like behaviors perturbed in D409V/null mice at 6 months. Gait and locomotion normal in homozygous KI mice at 8 and 12 months, but impaired gait in D409V/null mice as early as 3 months.

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Gba1 D409V KI Mouse (MJFF)

Observed

X
Dopamine Deficiency at 55

Dopamine levels did not differ at 4, 8, and 12 months of age, but dopamine turnover (ratio of DOPAC and HVA to dopamine) tended to increase, though the increase was only significant at 12 months of age.
X
Non-Motor Impairment at 54

Cognitive performance was impaired in 12-month-old heterozygous KI mice (but not at 3, 6, or 9 months), based on the Morris water maze and Y-maze. Anxiety-like behavior (based on the open-field test) did not differ at 12 months.
X
α-synuclein Inclusions at 54

Homozygous KI mice have higher levels of soluble monomeric α-synuclein in the hippocampus at 12 months than heterozygous KI mice and wild-type controls. Levels of pathologic phosphorylated form pS129 do not differ between homozygous KI mice and controls in the substantia nigra, cortex, or hippocampus.
X
Neuroinflammation at 54

Data are mixed on levels of GFAP and Iba-1 immunostaining in KI mice brain. One study in homozygous KI mice found no differences in the striatum and substantia nigra at 4, 8, or 12 months of age; another found decreased GFAP staining in the substantia nigra at 12 months; and a third study (het mice) found increased GFAP and Iba-1 in the hippocampus at 12 months.
X
Motor Impairment at 36

Homozygous D409V KI mice generally exhibit motor function similar to wild-type controls (open-field, Rotarod, grip strength, swim velocity). However, a couple of exceptions found in one study were greater grip strength force at 12 months of age and transiently increased locomotor activity on the open-field test at 8 months of age.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Gba1		Gba1: Knock-In	Parkinson's Disease	No deficits in dopaminergic neuron numbers in the substantia nigra pars compacta between homozygous KI mice and wild-type mice. Dopamine levels did not differ, but dopamine turnover (ratio of DOPAC and HVA to dopamine) tended to increase at older ages. Mixed findings on GFAP and Iba-1 staining across brain regions in KI mice.	Motor function is largely intact in KI mice, apart from transient increases in locomotor activity and increased grip strength at 8 and 12 months, respectively. Cognitive performance was impaired at 12 months of age, but not at younger ages. Anxiety-like behavior was not affected.

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Gba1 L444P KI Mouse (JAX)

Observed

X
α-synuclein Inclusions at 52

α-synuclein deposition reported in the striatum of 1-year-old mice in one study, but no differences in α-synuclein levels found in brain extracts of 6- and 14-month-old KI mice in another study.
X
Neuroinflammation at 53

Increased GFAP immunoreactivity observed in the striatum of 1-year-old mice in one study, but no differences in striatal GFAP or Iba-1 immunostaining observed in another study of 14-month-old KI mice.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Gba1		Gba1: Knock-In	Parkinson's Disease	No loss of dopaminergic cells in the substantia nigra at 14 months. Inconsistent results regarding α-synuclein deposition and striatal GFAP immunostaining.	No deficits in motor balance, as detected by Rotarod and balance beam tests, observed in 16-month-old L444P KI mice.

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Gba1 L444P KI Mouse (MMRRC)

Observed

X
Non-Motor Impairment at 13

Impaired contextual, but not cued, fear conditioning at 3 months of age in heterozygous KI mice. No deficits in olfaction (buried pellet test) or on the novel object recognition test at 24 months of age.
X
Neuroinflammation at 104

GFAP staining was comparable in heterozygous KI and wild-type mice at 8 and 24 months of age. Iba1 staining, however, was increased in 24-month-old heterozygous KI mice, but only in the granule cell layer of the olfactory bulb.
X
Mitochondrial Abnormalities at 35

By 8 months of age, heterozygous KI mice have impaired mitochondrial structure (smaller) and function (lower levels of mitochondrial DNA) in the midbrain. Mitochondrial function from cultured cortical neurons also impaired (increased reactive oxygen species generation, decreased mitochondrial complex I enzyme activity, decreased oxygen consumption rate).

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Gba1		Gba1: Knock-In	Parkinson's Disease	Dopaminergic neuron numbers are intact in the substantia nigra. Some alterations in soluble α-synuclein levels, but no findings of aggregation. Levels of dopamine and its metabolites are not perturbed in heterozygous KI mice. Neuroinflammation as measured by GFAP is not observed in heterozygous KI mice, but Iba1 staining may be increased in some regions.	Largely no differences in motor function between heterozygous KI and wild-type mice from 3 to 24 months of age. Impaired contextual, but not cued, fear conditioning at 3 months of age in heterozygous KI mice, but no deficits in olfaction or on the novel object recognition test at 24 months of age.

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HGBA L444P Tg on Gba1 KO Mouse

Observed

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
GBA1, Gba1		GBA1: Transgenic; Gba1: Knock-Out	Parkinson's Disease	Older mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system glucosylsphingosine, but not glucosylceramide, were noted.	No obvious phenotypic features noted.

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HGBA N370S Tg on Gba1 KO Mouse

Observed

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
GBA1, Gba1		GBA1: Transgenic; Gba1: Knock-Out	Parkinson's Disease	Older transgenic mice do not show evidence of neuropathology or α-synuclein inclusions. Significant progressive elevations in central nervous system glucosylsphingosine, but not in glucosylceramide, were noted.	No obvious features noted.

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LRRK2 R1441C KI Mouse

Observed

X
Non-Motor Impairment at 30

Acoustic startle reflex equal to wild-type mice at 12 months of age. Intracellular protein transport impaired in primary cultured cells. PKA activity is elevated in the striatum. Ciliation in striatal cholinergic neurons is decreased at 7 months of age and primary cilia formation is perturbed in the somatosensory cortex.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
LRRK2		LRRK2: Knock-In	Parkinson's Disease	No loss of dopaminergic (TH+) neurons in the substantia nigra pars compacta at 12 and 22 months. No loss of TH-immunoreactive neurons in the locus coeruleus. Basal levels of striatal dopamine, DOPAC, and HVA were comparable between KI and wild-type mice at 3, 12, and 23 months. However, evoked dopamine release in the striatum was reduced in adult heterozygous KI mice.	Acoustic startle reflex equal to wild-type mice at 12 months of age. Motor learning impaired upon antagonism of dopamine receptors (D1 and D2).

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LRRK2 G2019S KI Mouse

Observed

X
Non-Motor Impairment at 16

Altered responses to social-defeat stress (males, 3-4 mos) which correlated with changes in striatal plasticity and intrinsic membrane excitability. Attention deficits, slower information processing, impaired goal-directed learning in 2-6-month-old male KI mice, but cognitive flexibility and novel objective recognition are intact (2-6 mos). Perturbed sleep behavior at 8-10 mos.
X
Motor Impairment at 81

A battery of motor tests revealed no baseline deficits at 3-4, 12-13, and 18-19 months of age. However, an increased locomotor response after amphetamine challenge is observed at 18 months. Motor defects are exacerbated following a manganese stressor.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
LRRK2		LRRK2: Knock-In	Parkinson's Disease	Levels of phospho-substrates of LRRK2 (e.g., Rab10) are increased in the brain. Endocytosis and axonal transport defects in neurons. Cholinergic innervation density is lower in the prelimbic/infralimbic cortical areas and dorsomedial striatum, but not in the dorsal lateral geniculate nucleus in 2-6-month-old males. Microglial immunostaining is similar in the striatum and midbrain at 8 weeks	Attention deficits, slower information processing speeds, and impaired goal-directed learning are evident in 2-6-month-old mice—deficits rescued by systemic administration of the acetylcholinesterase inhibitor donepezil. Cognitive flexibility and novel objective recognition similar to controls. Sleep behavior is perturbed at 8-10 months of age.

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LRRK2 G2019S Mouse (BAC Tg)

Observed

X
Dopamine Deficiency at 52

Age-related decline in striatal dopamine content. Levels were decreased at 12 months of age, but not significantly different from controls at 6 months of age. Also, decreased dopamine metabolite homovanillic acid (HVA).
X
Non-Motor Impairment at 26

Tg mice spend less time in the REM sleep phase at 12 and 18 months of age. Age-dependent increase in plasma corticosterone (present starting at 6-8 months of age). Nuclear envelope integrity is perturbed in dopaminergic neurons at 12 months.
X
Neuroinflammation at 8

Application of α-synuclein fibrils leads to exacerbated responses (more inclusions and greater infiltration of pro-inflammatory monocytes).
X
Motor Impairment at 78

Behavior in hemizygous mice was comparable to littermate controls in terms of activity levels (open-field test) and coordination (beam-walk test) at 6 and 12 months, , but not at 18 months of age, when Tg mice develop motor deficits (Rotarod).
X
Mitochondrial Abnormalities at 0

Primary cultured cells from Tg mice exhibit mitochondrial fragmentation and membrane depolarization.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
LRRK2	LRRK2 G2019S	LRRK2: Transgenic	Parkinson's Disease	Brain appears normal. No neuronal or cell death at 12 months. Impaired neurite motility and synaptic vesicle endocytosis in cultured neurons. No increase in α-synuclein or ubiquitin levels or aggregation; however, cultured neurons developed more inclusions when exposed to exogenous α-synuclein fibrils. Decreased striatal dopamine content, decreased evoked release.	Apparently normal behavior. No change in activity level or motor coordination at 12 months. Motor deficits appear at 18 months.

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LRRK2 G2019S Mouse (Tg)

Observed

X
Non-Motor Impairment at 45

Anxiety/depression-like symptoms were observed at 10-12 months of age.
X
α-synuclein Inclusions at 52

Around 2 years of age, mice did not exhibit abnormalities in α-synuclein in the ventral midbrain, striatum, or cerebral cortex. However, one study found α-synuclein accumulation in whole brain lysates of 12- to 19-month-old transgenic mice.
X
Neuroinflammation at 63

Around 2 years of age, mice did not have GFAP abnormalities in the ventral midbrain, striatum, or cerebral cortex. However, activated microglia were reported in the striatum at 14 months, and CD68 and TNF-α levels were increased in whole brains at 4-6 months. Others have not observed differences in Iba-1 staining (microglial marker) at 6, 12, or 18 months in the striatum or substantia nigra.
X
Motor Impairment at 35

Rotarod performance deteriorated in 14- to 18-month-old mice, but minor deficits are already observed as early as 8 months of age. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex.
X
Mitochondrial Abnormalities at 63

Increased numbers and condensation of mitochondria in striatal microglia were reported at 14 months. Abnormally high levels of condensed mitochondria were also observed in cortical and striatal neurons at 17-18 months.
X
Neuronal Loss at 83

By 19-21 months, mice lose 18 percent of TH-positive dopaminergic neurons in the substantia nigra pars compacta and 14 percent of dopaminergic dendrites in the substantia nigra pars reticulata. At 1-2 months neuronal numbers were normal. Some authors do not see differences in TH staining up to 2 years of age. No abnormal neuronal loss is observed in the ventral tegmental area or cerebellum.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
LRRK2	LRRK2 G2019S	LRRK2: Transgenic	Parkinson's Disease	Age-dependent dopaminergic neuron degeneration in the substantia nigra, though reports are mixed. No reduction in striatal dopaminergic terminals or dopamine levels. Some reports of α-synuclein accumulation. Abnormal mitochondria in striatal neurons and microglia; accumulation of autophagic vacuoles. Evidence for activated striatal microglia and increased levels of CD68 and TNF-α in whole brain.	Deterioration of Rotarod performance in 14- to 18-month-old mice. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex. Anxiety/depression-like symptoms at 10-12 months.

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LRRK2 G2019S Rat (BAC Tg)

Observed

X
Non-Motor Impairment at 26

Bone marrow myeloid progenitor numbers were decreased, but suppressive myeloid cells were increased at 6 to 11 months of age
X
Motor Impairment at 35

Mild abnormalities in motor behavior. Slightly more postural instability at 8 months of age (but not at 4 and 12 months). Slightly more rearing events at 12 months, but not at younger ages.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
LRRK2	LRRK2 G2019S	LRRK2: Transgenic	Parkinson's Disease	No overt neurodegeneration out to 12 months of age. Elongated dopaminergic neurons. Elevated oxidative and nitrosative stress. No evidence of gliosis. No α-synuclein inclusions until challenged with exogenous α-synuclein. No change in dopamine levels.	Mild abnormalities in motor behavior. Slightly more postural instability at 8 months of age (but not at 4 and 12 months). Slightly more rearing events at 12 months, but not at younger ages.

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Lrrk2 KO Mouse

Observed

X
Neuroinflammation at 87

Striatal staining of GFAP, a marker of reactive astrocytosis, did not differ between control and KO mice, but cells positive for Iba1 staining, a marker of activated microglia, were moderately enlarged in the striatum of 20 -month-old KO mice. Cx3cr1 mRNA levels higher in KO mouse brains.
X
Motor Impairment at 52

Motor behavior is generally intact up to 18 months based on Rotarod and open field tests. However, some age-dependent effects are observed on the open field test: 12 -month-old mice traveled longer distances and had higher walking speeds versus controls, which was not apparent in 3- or 24-month-old mice. Older (24 months) mice had deficits in motor skill learning as measured by Rotarod.
X
Mitochondrial Abnormalities at 9

Adult (9 - to 23-week-old) Lrrk2 KO mice exhibit enhanced mitophagy in dopaminergic neurons of the substantia nigra pars compacta, as detected by an increase in the number of mitolysosomes.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Lrrk2		Lrrk2: Knock-Out	Parkinson's Disease	No loss in the number of TH–positive cells in the substantia nigra pars compacta up to 24 months. Cerebral cortex and dorsal striatum volumes reduced at 12 months. Striatal spiny projection neurons were enlarged and the frequency of nuclear invaginations was increased at 12 months, suggesting premature aging. Dendritic morphology perturbed at 12 months.	No differences between KO and wild-type mice up to 24 months on several behavioral tests, including the elevated plus maze for anxiety-like behavior, the buried treat test to measure hyposmia, the grip strength test for forelimb strength, or working memory as measured by spontaneous alternation. Older (24-month-old) mice showed deficits in motor skill learning as measured by Rotarod.

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Lrrk2 KO Rat

Observed

X
Non-Motor Impairment at 5

Abnormalities occur in peripheral organs, most notably the kidney, but also the liver, lung, and spleen. Changes are progressive, although they do not appear to shorten lifespan. The earliest reported alterations occur in the kidneys at 1 month of age.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Lrrk2		Lrrk2: Knock-Out	Parkinson's Disease	Not observed. Protection against dopaminergic cell loss under conditions involving LPS or α-synuclein overexpression in the substantia nigra. No changes in basal or evoked release of dopamine.	One assessment of Rotarod performance revealed no impairment at 12 months of age compared with wild-type rats.

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LRRK2 R1441C Mouse (Tg - Conditional)

Observed

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
LRRK2	LRRK2 R1441C	LRRK2: Transgenic	Parkinson's Disease	No neurodegeneration in the brain. No proteinaceous inclusions of α-synuclein, ubiquitin, or tau. No reactive gliosis. No change in dopamine levels. Subtle morphological abnormalities in dopaminergic and non-dopaminergic neuronal nuclei, including altered nuclear envelope.	No overt behavioral differences. Activity levels and Rotarod performance are normal into advanced age.

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LRRK2 WT Mouse (BAC Tg)

Observed

X
Dopamine Deficiency at 52

Striatal dopamine levels, as measured by PET imaging with [18F]FDOPA uptake, are higher in WT-OX versus non-Tg mice.
X
Motor Impairment at 52

WT-OX mice (12 months) are hyperactive on several parameters of the open-field test. Gait analysis (Cat-Walk system) was also perturbed relative to non-Tg controls. However, the number of rears did not differ.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
LRRK2		LRRK2: Transgenic	Parkinson's Disease	Overtly normal brain structure. Intact, but shorter, neurites.	Motor hyperactivity at 12 months of age.

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MCI-Park Mouse

Observed

X
Dopamine Deficiency at 5

Profound loss of evoked dopamine release in the dorsolateral striatum as early as 30 days. In contrast, somatodendritic dopamine release in the SN did not differ between genotypes at 30 days, but was dramatically reduced by 60 days.
X
Non-Motor Impairment at 2

Impaired associative learning (Y-maze test) at 30 days . Impaired sleep functions starting at 6 weeks of age, with significantly altered sleep-wake patterns (total, NREM, and REM sleep), increased sleep fragmentation, and altered EEG activity.
X
Motor Impairment at 6

Striatal motor learning (adhesive removal test) was impaired starting at 30 days. Rearing in the cylinder testing was impaired at 40 days. Total distance travelled was decreased by 60 days on the open-field test. By 100 days, splayed hindlimbs, abnormal paw placement, and alterations in stride observed.
X
Mitochondrial Abnormalities at 3

By 20 days mitochondria were in an oxidative phosphorylation deficit. Altered mitochondria structure, but not mitochondrial density, was observed at 35 days in dopaminergic neurons of the SN. Metabolic reprogramming to a glycolytic-predominant state of mitochondria was indicated by alterations in expression of genes and functional pharmacologic experiments.
X
Neuronal Loss at 4

TH expression decreased at 30 days in the dorsal striatum. By age 60 days, TH expression decreased in substantia nigra dopaminergic neurons. No neurodegeneration was observed in axons, cell bodies, or dendritic arbors of SN dopaminergic neurons at 60 days. By 120 to 150 days, neurodegeneration is present and about 40% of SN dopaminergic neurons are lost.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
		Conditional Knock-out	Parkinson's Disease	Progressive reductions in TH expression in the striatum and SN. Overt neuron loss in the SN only at older ages (>120 days). Electrophysiological measurement of SN dopaminergic neurons showed altered pacemaking activity and burst spiking. Altered expression of many neuronal genes. Loss of evoked dopamine release in the dorsolateral striatum at 30 days of age.	Impaired associative learning and striatal motor learning at 30 days. Impaired rearing at 40 days. Decreased total distance travelled by 60 days. By 100 days, splayed hindlimbs, abnormal paw placement, and alterations in stride. Impaired sleep functions starting at 6 weeks.

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Parkin KO Rat

Observed

X
Non-Motor Impairment at 9

Orientation to an olfactory stimulus was normal. At 2 months of age, male KO rats had a greater preference for methamphetamine than wild-type rats based on self-administration and place preference tests.
X
Mitochondrial Abnormalities at 14

Alterations in mitochondrial protein expression in synaptic and nonsynaptic striatal samples of 3-month-old KO rats.
X
Neuronal Loss at 35

A small, non-significant reduction in dopaminergic neurons was observed in the substantia nigra at 8 months of age.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Park2		Park2: Knock-Out	Parkinson's Disease	No significant changes in dopaminergic neurons in the substantia nigra nor striatal dopamine levels, but alterations in dopaminergic signaling were detected at an early age, as were disruptions in mitochondrial protein expression in striatum. No increase in α-synuclein. Evoked release of striatal glycine greater at 12 months versus wild-type rats.	No behavioral deficits detected at 4, 6, and 8 months of age. However, at 2 months, male KO rats made fewer small stereotypic movements, such as scratching and grooming, than wild-type controls. At 2 months, male KO rats had a greater preference for methamphetamine than wild-type rats.

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Parkin Q311X Mouse (BAC Tg)

Observed

X
Dopamine Deficiency at 69

Surviving nigral neurons at 16 months of age had reduced tyrosine hydroxylase expression. By 19-21 months, striatal concentrations of dopamine and the dopamine metabolite DOPAC were decreased compared with non-Tg littermates.
X
Non-Motor Impairment at 68

Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.
X
Non-Motor Impairment at 71

Autophagy and lysosomal dysfunction in mutant mice at 16-17 months of age.
X
α-synuclein Inclusions at 72

Lewy body-like inclusions were not observed at any age, however, mutant mice exhibit age-dependent accumulation of proteinase-K resistant endogenous α-synuclein in the substantia nigra at 16 months of age.
X
Motor Impairment at 70

Behavior was fairly normal at 3 months, but motor abnormalities were detected by 16 months of age, including hypoactivity and deficits in coordination and in motor response to sensory stimuli.
X
Mitochondrial Abnormalities at 4

Mitochondrial dysfunction observed as early as 1 month of age, based on electron microscopy (e.g., lacking an outer membrane, swollen) and expression of the short isoform of OPA1.
X
Neuronal Loss at 26

Progressive loss of dopaminergic neurons in the substantia nigra, starting as early as 6 months of age. About 40 percent loss by 16 months of age with a corresponding decrease in dopaminergic projections to the striatum. Neurons in the ventral tegmental area were relatively spared.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Park2	Parkin Q311X	Park2: Transgenic	Parkinson's Disease	Degeneration of dopaminergic neurons in the SN and nerve terminals in the striatum. Reduced dopamine in the striatum. Accumulation of proteinase-K resistant α-synuclein and oxidative protein damage. Dysfunction in the burst-firing pattern activity of dopaminergic SN neurons and increased expression of markers for excitotoxic damage.	Late-onset hypoactivity (about 16 months of age), other modest changes in motor behavior and coordination in tests that included traversing a beam or removing adhesive.

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Parkin S65A KI Mouse

Observed

X
Motor Impairment at 53

Impaired performance on the raised balance beam at 12 and 18 months of age in homozygous KI mice. No deficits in Rotarod performance or gait analysis.
X
Mitochondrial Abnormalities at 52

Mitochondrial respiration (respiratory control ratio) was impaired in an age-dependent manner—at 12 months, but not at 3 months—in homozygous KI mice. No deficits in basal mitophagy.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Park2	Park2 S65A	Park2: Knock-In	Parkinson's Disease	No evidence of nigrostriatal neuropathology in 18-month-old homozygous mice.	Motor dysfunction on the raised balance beam by 12 months of age. No deficits in Rotarod performance or gait.

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PINK1 G309D (PINK1-/-) Mouse (KI)

Observed

X
Dopamine Deficiency at 39

Decreased dopamine concentration in the striatum by 9 months of age.
X
Neuroinflammation at 81

Expression of factors involved in Toll-like receptor signaling were increased in the cerebellum, as were astrocytic and microglial markers in the corticospinal tract and striatum at 18 months.
X
Motor Impairment at 70

At 16 months of age Pink1^-/- mice exhibited decreased spontaneous locomotor activity. Strength and coordination were intact.
X
Mitochondrial Abnormalities at 13

By 3 months of age the mice exhibited a mitochondrial import defect. This phenotype was more severe at 6 months and import was reduced nearly 50% by 12 months of age. By 6 months, ATP production, respiration, and mitochondrial membrane potential were also reduced.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
PINK1	Pink1 G309D	PINK1: Knock-In	Parkinson's Disease	No neuronal loss. No Lewy bodies or α-synuclein aggregates, but α-synuclein expression change in brainstem/midbrain. Low dopamine levels. Mitochondrial dysfunction (e.g., reduced ATP, reduced respiratory activity). Increase in factors involved in Toll-like receptor signaling in the cerebellum, and increased astrocytic and microglial markers in the corticospinal tract and striatum.	Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination.

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PINK1 KO Mouse

Observed

X
Non-Motor Impairment at 0

Modest vocalization deficits observed at 4-6 months. Reduced BDNF levels in the midbrain and cortex at 10 months. Cardiac hypertrophy observed at 2 and 6 months of age.
X
Motor Impairment at 23

Reduced spontaneous locomotor activity and skill reported at 3-6 months.
X
Mitochondrial Abnormalities at 9

Altered shape, density, and movement of dendritic mitochondria observed in cultured primary neurons from embryonic mice. Also, an abnormal rise in serum cytokines in response to acute mitochondrial stress was reported in vivo. By 2 months of age, mitochondrial dysfunction observed in cardiomyocytes.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Pink1		Pink1: Knock-Out	Parkinson's Disease	Normal numbers of dopaminergic neurons and tyrosine hydroxylase levels in substantia nigra at 8-9 months of age. Alterations in the dendrites of midbrain dopaminergic neurons and cultured cortical neurons. Altered shape, density, and movement of dendritic mitochondria in cultured primary neurons from embryonic mice. Reduced BDNF levels in the midbrain and cortex at 10 months.	Reduced spontaneous locomotor activity and skill at 3-6 months. Modest vocalization deficits at 4-6 months.

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Pink1 KO Rat

Observed

X
Non-Motor Impairment at 9

Nociception alterations in male KO rats observed at 6 to 10 months of age, indicating thermal hyperalgesia. This effect was present in female KO rats at 2 months of age, but not at older ages. Abnormalities in ventilation frequency were also observed in male KO rats. Defects in ultrasonic vocalizations starting at 2 months of age in male and female KO rats.
X
α-synuclein Inclusions at 18

Alpha-synuclein aggregates were found as early as 4 months of age and increased in number up to 12 months. Areas affected include the periaqueductal gray, substantia nigra pars compacta, locus coeruleus, nucleus ambiguous, cortex, thalamus, and striatum.
X
Motor Impairment at 5

Abnormalities in gait, coordination, and strength. By 5 weeks, KOs had increased foot slips on the tapered balance beam, at 7 weeks they showed hind limb fatigue, which progressed to hind limb dragging, and by 2 months they exhibited alterations in oromotor behaviors. Deficits in gait may be transient. Partial reversal of motor impairment by Levodopa.
X
Mitochondrial Abnormalities at 18

Alterations in mitochondrial metabolites and mitochondrial protein expression were reported as early as 4 months of age in cortex and striatum. Oxygen consumption rates were elevated in striatal mitochondria isolated from 9-month-old rats, but not in non-synaptic samples from 3-month-old rats.
X
Neuronal Loss at 11

Age-related decrease in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra. A reduction of 25 and 50 percent at 6 months and 8 months, respectively. Deficits in TH staining in the substantia nigra have been observed as early as at 2.5 months of age. While some studies did not see any changes in TH-positive cells in the striatum, others have observed a 15% loss.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Pink1		Pink1: Knock-Out	Parkinson's Disease	Age-related decrease in dopaminergic neurons in the substantia nigra; greater than 50 percent reduction at eight months. Alterations in striatal dopamine and serotonin levels. Progressive increase in α-synuclein aggregates and reduced brain volume across numerous regions. Increased ventricular volume. Alterations in cortical and striatal mitochondria.	Abnormalities in gait, coordination, and strength. As early as 5 weeks of age, KOs had increased foot slips on the tapered balance beam, at 7 weeks they showed hind limb fatigue, which progressed to hind limb dragging, and by 2 months they exhibited alterations in oromotor (lingual) behaviors.

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Thy1-αSyn “Line 61” Mouse

Observed

X
Dopamine Deficiency at 63

Line 61 mice lose striatal dopamine progressively, starting at about 14 months of age. Between approximately 6 and 10 months, however, the neurotransmitter’s extracellular levels are transiently increased.
X
Non-Motor Impairment at 11

Disruptions in olfaction, circadian rhythms, sleep, cognition, social behavior, and autonomic function have been reported. Several are reminiscent of PD non-motor impairments. Alterations in olfaction, circadian rhythms, and the autonomic regulation of heartrate occur as early as 3 months of age.
X
α-synuclein Inclusions at 4

Proteinase K-resistant aggregates are seen at 1 month and increase with age, including the substantia nigra, periqueductal gray, cortex, striatum, vagus, olfactory bulb, thalamus, locus coeruleus, and cerebellum, as well as cholinergic neurons in the colon. Elevated levels of phospho-serine 129 α-synuclein are found in the substantia nigra, striatum, cortex, frontal cortex, and hippocampus.
X
Neuroinflammation at 5

Neuroinflammation markers have been seen in the cortex, striatum, substantia nigra, and hippocampus. The time course and profile vary between brain regions and some features remain subject to debate. However, neuroinflammation appears to affect the striatum first (1 month), and then the substantia nigra (5–6 months). At older ages, particularly in the substantia nigra, inflammation attenuates.
X
Motor Impairment at 4

Impairments in balance, coordination, muscle strength, fine motor skills, vocalizations, and stress-induced defecation arise between 1 and 3 months. Transient hyperactivity is seen between 4 and 9 months of age, followed by hypoactivity and sensorimotor deficits at about 15 months. As the phenotype becomes more severe, the mice develop difficulty eating, akinesia, and hunched posture.
X
Mitochondrial Abnormalities at 18

The functions of mitochondrial respiratory complexes in midbrain and striatum are impaired, with the earliest reported deficit affecting complex I in the midbrain at 4 months. Elevated α-synuclein accumulation was found in mitochondria of the midbrain, striatum, and cortex.
X
Neuronal Loss at 16

Although neuron loss occurs in the neocortex and hippocampal CA3 region as early as 3–4 months of age, there is no reduction in the PD-relevant dopaminergic neurons of the substantia nigra, even at 22 months of age.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
SNCA		SNCA: Transgenic	Parkinson's Disease

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Vps35 p.D620N KI Mouse

Observed

X
Dopamine Deficiency at 13

Enhanced peak amplitude in dopamine release and prolonged reuptake kinetics in acute striatal slices from 3-month-old mice; decreased DAT and increased VMAT2. Basal levels of dopamine and metabolites in dorsolateral striatum did not differ, but the DOPAC+HVA/DA ratio was increased. At 16 months, dopamine in striatal homogenates was reduced, but levels of metabolites (DOPAC, HVA) did not differ.
X
α-synuclein Inclusions at 65

No differences in α-synuclein puncta density or distribution in the SNpc at 3 months. No pathological α-synuclein observations seen throughout the brain at 13 months. However, at 15 to 16 months, increased somatic α-synuclein immunoreactivity found in the SNpc, and increased α-synuclein oligomers and aggregated α-synuclein observed in the ventral midbrain.
X
Neuroinflammation at 64

Increased GFAP immunostaining in the SNpc, but not in the striatum, of 15- to 16-month-old VKI mice; no GFAP differences observed at earlier ages. No differences in microgliosis (Iba-1 immunostaining) in the SNpc or the striatum up to 16 months of age.
X
Motor Impairment at 60

Motor deficiencies on the open-field test and the beam walking test appear at 14 months of age, but not earlier from 3 to even 13 months of age. However, performance on other motor tests—Rotarod and grip strength—did not differ at the advanced age (14 months). No deficits seen in the cylinder test (rearing) at 3 months. Amphetamine-induced hyperlocomotion is rescued by LRRK2 kinase inhibition.
X
Mitochondrial Abnormalities at 61

Mitochondrial structure, assesed by EM, was perturbed at 14 months, but not at 3 months, of age. Mitochondrial function—namely, the oxygen consumption rate—was reduced in older (15-month-old) mice.
X
Neuronal Loss at 56

Loss of TH-positive neurons in the SNpc and loss of TH-positive nerve terminals in the striatum at 13-16 months. Widespread axonal degeneration in the brain at 13 months.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
Vps35		Vps35: Knock-In	Parkinson's Disease	Loss of TH+ neurons in SNpc and TH+ terminals in striatum at 13-16 mos. Widespread axonal degeneration at 13 mos. Increased somatic α-synuclein in SNpc; α-synuclein oligomers and aggregates in ventral midbrain at 15-16 mos. Increased somatodendritic tau/p-tau with age, but no neurofibrillary pathology. Increased GFAP in SNpc, but not striatum at 15-16 mos. No microgliosis up to 16 mos.	No deficits in the buried pellet test, measuring olfactory function, from 6-14 months. Deficits in mood (anxiety/apathy) and/or cognition on elevated plus maze, starting at 3 months (unpublished).

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α-synuclein A30P/A53T Mouse (Tg)

Observed

X
Dopamine Deficiency at 9

Striatal dopamine concentrations were lower at all ages tested, including the earliest age, 2-3 months. Dopamine concentrations dropped with age, and levels of metabolites (e.g., DOPAC and HVA) were also lower in HM2 mice than non-Tg by 13-23 months of age.
X
Motor Impairment at 30

At young age 2-3 months, HM2 mice were more active than non-Tg controls, but by middle age (7-9 months) they were less active. At advanced ages (13-23 months), they also exhibited impaired coordination as measured by the time it took to right themselves from an inverted wire screen. However, no deficiencies in Rotarod performance, grip strength, or open-field movements were detected at 6 months.
X
Neuronal Loss at 34

Progressive loss of dopaminergic neurons was reported in the substantia nigra pars compacta (19 percent reduction at 8.5 months and 55 percent at 19 months).

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
SNCA	SNCA A30P, SNCA A53T	SNCA: Transgenic	Parkinson's Disease	Progressively loss of dopaminergic neurons in the substantia nigra pars compacta, observed by 8.5 months. No α-synuclein inclusions. Morphological abnormalities in the dopaminergic system, including axonal and dendritic abnormalities, reduced dopamine concentration in the striatum.	More active as young adults, then hypoactive compared to non-Tg. Also reduced motor coordination in old age as measured by the time to right from an inverted wire screen.

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α-synuclein A53T Mouse (Tg)

Observed

X
Dopamine Deficiency at 23

In symptomatic mice, striatal dopamine and metabolites DOPAC and HVA are comparable to wildtype, but at 5 months, striatal tyrosine hydroxylase is reduced. Increased D1 receptors in the substantia nigra and decreased dopamine transporters in the nucleus accumbens and striatum have been reported.
X
Non-Motor Impairment at 50

At 11–12 months, spatial memory was impaired as assessed by the Barnes circular maze.
X
α-synuclein Inclusions at 35

Prior to motor deficits, these mice develop accumulations of α-synuclein in select neuronal populations, including the midbrain, cerebellum, brainstem, and spinal cord. The protein aggregates do not resemble Lewy bodies, but are thioflavin-S-positive, indicating fibrillar structure.
X
Neuroinflammation at 40

In symptomatic mice, increased GFAP immunoreactivity was observed in select brain regions, including the dorsal midbrain, deep cerebellar nuclei, brainstem, and spinal cord. Cortex, hippocampus, and substantia nigra did not have increased reactivity compared with non-Tg controls.
X
Motor Impairment at 32

These mice develop severe motor impairment starting around 9-16 months of age. The deficits start out with mild hyperactivity at 7 months and progress to a wobbling movement, decreased activity, and ultimately paralysis and death.
X
Mitochondrial Abnormalities at 56

At 11–14 months, mitochondria in brainstem neurons were enlarged and their co-localization with the mitochondrial fission protein Drp1 was reduced.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
SNCA	SNCA A53T	SNCA: Transgenic	Parkinson's Disease	No overt neuronal loss. Alterations in dopaminergic-associated proteins in the striatum, substantia nigra, and nucleus accumbens. Region-specific neuronal accumulation of fibrillar α-synuclein, ubiquitin, and neurofilament-H, and accompanying astrocytosis.	Early hyperactivity followed by severe motor impairment, manifesting as wobbling, posturing, decreased spontaneous locomotor behavior, inability to navigate the Rotarod, and ultimately paralysis and death. At 11–12 months, spatial memory impaired as assessed by the Barnes circular maze.

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α-synuclein A53T Mouse (Tg) on SNCA KO

Observed

X
Non-Motor Impairment at 14

By 3 months of age, the mice develop gastrointestinal dysfunction.
X
Motor Impairment at 26

By 6 months of age, homozygous mice became hypoactive, traveling less distance. This was not attributed to changes in exploratory behavior caused by anxiety. Also at 6 months, differences in performance on the accelerating Rotarod were seen.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
SNCA	SNCA A53T	SNCA: Transgenic; SNCA: Knock-Out	Parkinson's Disease	No loss of dopaminergic neurons in the substantia nigra by 18 months of age. Rare dystrophic synapses in the hippocampus at advanced age, but no Lewy body-like pathology or α-synuclein aggregation in the brain. No change in striatal dopamine concentration.	Impaired performance on the Rotarod and reduced spontaneous locomotor activity in open-field test.

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α-synuclein E46K Rat (BAC Tg)

Observed

X
α-synuclein Inclusions at 52

By 12 months of age, intracellular aggregates were observed in dopaminergic neurons of the substantia nigra and ventral tegmental area. Aggregates noted to be fairly small compared to those observed in PD brain. In the striatum and cortex α -synuclein accumulation appeared primarily in neuronal processes.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
SNCA	SNCA E46K	SNCA: Transgenic	Parkinson's Disease	No overt neuronal loss. Accumulation of mutant α-synuclein in the brain, in the form of diffuse staining and intracellular aggregates. Aggregates were largely restricted to dopaminergic neurons of the substantia nigra and ventral tegmental area. Elevated nitrotyrosine in dopaminergic neurons.	No overt behavioral changes until challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity.

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α-synuclein KO Mouse

Observed

X
Neuroinflammation at 16

Microglia cultured from Snca KO brain were more reactive, ramified. They had vacuole-like structures. Snca KO microglia exhibited exacerbated response to LPS, with greater secretion of pro-inflammatory cytokines.
X
Motor Impairment at 26

Motor function was largely intact. Normal performance on the Rotarod and in total distance travelled in the open field test. Subtle differences only (e.g., less rearing behavior than controls). They also spent less time in the center of the field, suggesting a possible anxiety-related phenotype.
X
Mitochondrial Abnormalities at 39

Mitochondrial abnormalities include reduced levels of the mitochondrial phospholipid cardiolipin and reduced activity of electron transport chain complex I/III.

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
SNCA		SNCA: Knock-Out	Parkinson's Disease	No gross brain abnormalities. Electron microscopy revealed synaptic vesicle abnormalities in hippocampal neurons, i.e., fewer vesicles in the reserve pool.	Behavior is largely normal. Normal performance on the Rotarod. Subtle differences in locomotor activity (e.g., less rearing) but normal overall distance travelled. Learning and memory appear intact. Possible anxiety-like phenotype.

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α-synuclein KO Mouse (Conditional)

Observed

Absent

No Data

Genes	Mutations	Modification	Disease	Neuropathology	Behavior/Cognition
SNCA		SNCA: Conditional Knock-out	Parkinson's Disease	No data.	No data.

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32 Models

32 Visualizations

Phenotypes Examined

Observed

Neuroinflammation at 4

Motor Impairment at 39

Neuronal Loss at 52

Absent

Dopamine Deficiency at

α-synuclein Inclusions at

No Data

Non-Motor Impairment at

Mitochondrial Abnormalities at

Observed

Non-Motor Impairment at 17

Motor Impairment at 17

Mitochondrial Abnormalities at 13

Neuronal Loss at 26

Absent

Dopamine Deficiency at

α-synuclein Inclusions at

No Data

Neuroinflammation at

Observed

Non-Motor Impairment at 17

α-synuclein Inclusions at 18

Motor Impairment at 14

Absent

Neuroinflammation at

Neuronal Loss at

No Data

Dopamine Deficiency at

Mitochondrial Abnormalities at

Observed

Dopamine Deficiency at 55

Non-Motor Impairment at 54

α-synuclein Inclusions at 54

Neuroinflammation at 54

Motor Impairment at 36

Absent

Neuronal Loss at

No Data

Mitochondrial Abnormalities at

Observed

α-synuclein Inclusions at 52

Neuroinflammation at 53

Absent

Motor Impairment at

Neuronal Loss at

No Data

Dopamine Deficiency at

Non-Motor Impairment at

Mitochondrial Abnormalities at

Observed

Non-Motor Impairment at 13

Neuroinflammation at 104

Mitochondrial Abnormalities at 35

Absent

Dopamine Deficiency at

α-synuclein Inclusions at

Motor Impairment at

Neuronal Loss at

No Data

Observed

Absent

α-synuclein Inclusions at

Motor Impairment at

Neuronal Loss at

No Data

Dopamine Deficiency at

Non-Motor Impairment at

Neuroinflammation at

Mitochondrial Abnormalities at

Observed

Absent

α-synuclein Inclusions at

Motor Impairment at

Neuronal Loss at

No Data

Dopamine Deficiency at