Species: Rat
Genes: LRRK2
Mutations: LRRK2 G2019S
Modification: LRRK2: Transgenic
Disease Relevance: Parkinson's Disease
Strain Name: NTac:SD-Tg(LRRK2*G2019S)571CJLi
Genetic Background: Sprague-Dawley
Availability: Available through Taconic, Cat# 10681, Cryopreserved. Research services with this model are available from Scantox Neuro.

Summary

This transgenic (Tg) rat model overexpresses mutant Lrrk2. It was originally developed in the laboratory of Chenjian Li and then re-derived at Taconic with the support of the Michael J. Fox Foundation.

This model expresses high levels of mutant Lrrk2 in the brain. An early study found approximately 20 to 30 times more Lrrk2 in Tg rats than in non-Tg rats. However, as the BAC line stabilized, expression levels have stabilized at about afourfold increase over endogenous levels (Andrew West, personal communication, Feb 2017). Expression was highest in the striatum and cortex. In contrast to nonTg rats, in which cortical expression of Lrrk2 is largely restricted to layer V, Tg rats exhibit expression in layers II-V. In the midbrain, Lrrk2 expression was seen in dopaminergic neurons of the substantia nigra pars compacta (SNpc), but not in the SN pars reticulata. In the striatum, scattered large neurons were strongly positive for Lrrk2 protein (West et al., 2014).

Another study found Lrrk2 expression levels to be five to eight times greater in Tg rats than in non-Tg rats at 8 months of age. Again, clear expression was observed in the cortex and ventral midbrain, including in the SNpc. In the midbrain, Lrrk2 expression was highly co-localized with dopaminergic neurons, that is, neurons co-labeling with tyrosine hydroxylase (TH) (Lee et al., 2015).

It is important to note that markers of LRRK2 kinase activity, like pS1292-LRRK2 or phosphorylated Rab proteins, have not yet been established in brain tissue (Andrew West, personal communication, January 2024). Also, despite high levels of Lrrk2 overexpression, these rats do not develop overt loss of dopaminergic neurons in the SN or striatum out to 12 months of age. They similarly do not develop gross changes in cellular morphology, although quantitative morphometric analysis revealed dopaminergic neurons in the SNpc to be abnormally elongated compared with nonTg neurons. Total cell body area was not significantly affected (Lee et al., 2015). Neurodegeneration could be elicited in 10 to 12 week-old rats by intracranial injection of recombinant adeno-associated viral vectors (AAV) expressing human α-synuclein (Daher et al., 2015).

Following a lipopolysaccharide (LPS) challenge into the SNpc, LRRK2 G2019S rats also exhibited an increased pro-inflammatory response compared with non-Tg animals (Moehle et al., 2015). They showed an increase in the intensity and proportion of CD68+ cells and a reduction in TH cells. However, at baseline, there were no neuroinflammation-related differences in the SNpc between LRRK2 G2019S and non-Tg rats.

Tg rats exhibited elevated levels of oxidative and nitrosative stress in the midbrain. Specifically, individual nigral dopaminergic neurons in Tg rats had a higher ratio of oxidized (S-S) thiols to reduced (SH) thiols compared with nonTg controls. Similarly, levels of 3-nitrotyrosine (3-NT) in dopaminergic neurons of the SN were increased nearly twofold in Tg rats. Levels of iNOS expression were elevated in nigral dopaminergic neurons, suggestive of neuroinflammation. However, there were no detectable differences in microglia density in the SN or in the morphology of Iba-1 positive cells at 12 months of age. Similarly, there was no change in the number of reactive astrocytes as assessed by GFAP staining in the SN (Lee et al., 2015).

In the striatum, expression of G2019S Lrrk2 in Tg rats did not induce changes in dopamine levels, nor in the levels of dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), or the rate of dopamine turnover in 8- and 12-month-old rats. At 12 months of age, Tg rats exhibited significantly more homovanillic acid (HVA). Serotonin levels in the striatum were unchanged. The density of dopaminergic terminals in the striatum were unchanged (Lee et al., 2015).

Under basal conditions, these rats do not develop α-synuclein inclusions. However, they demonstrated a greater propensity to develop inclusions when α-synuclein fibrils, but not monomers, were injected in the SNpc (Volpicelli-Daley et al., 2016), although this finding was not reproducible (Andrew West, personal communication, January 2024).

With regard to immune function in 6- to 11-month-old LRRK2 G2019S rats, compared with control rats, bone marrow myeloid progenitor numbers were decreased, but suppressive myeloid cells in the periphery were increased, which can result in suppressed Th17 cell differentiation (Park et al., 2017).

Behaviorally, these rats exhibit mild age-specific motor abnormalities. In terms of postural instability, they were comparable to nonTg rats at 4 and 12 months of age, with slightly more instability at 8 months of age. In a rearing test, they reared a comparable number of times to nonTg rats at 4 and 8 months of age, but exhibited significantly more rearing events at 12 months of age than nonTg controls (Lee et al., 2015).

The above description refers to hemizygous rats.

Modification Details

These rats carry a BAC construct contianing the human gene Lrrk2 with the gain-of-function G2019S mutation, in addition to the endogenous rat Lrrk2 gene (Scantox Neuro [formerlyQPS Austria]).

Phenotype Characterization

Q&A with Model Creator

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References

Paper Citations

1. West AB, Cowell RM, Daher JP, Moehle MS, Hinkle KM, Melrose HL, Standaert DG, Volpicelli-Daley LA. Differential LRRK2 expression in the cortex, striatum, and substantia nigra in transgenic and nontransgenic rodents. J Comp Neurol. 2014 Aug 1;522(11):2465-80. Epub 2014 Apr 12 PubMed.
2. Lee JW, Tapias V, Di Maio R, Greenamyre JT, Cannon JR. Behavioral, neurochemical, and pathologic alterations in bacterial artificial chromosome transgenic G2019S leucine-rich repeated kinase 2 rats. Neurobiol Aging. 2015 Jan;36(1):505-18. Epub 2014 Jul 15 PubMed.
3. Daher JP, Abdelmotilib HA, Hu X, Volpicelli-Daley LA, Moehle MS, Fraser KB, Needle E, Chen Y, Steyn SJ, Galatsis P, Hirst WD, West AB. Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration. J Biol Chem. 2015 Aug 7;290(32):19433-44. Epub 2015 Jun 15 PubMed.
4. Moehle MS, Daher JP, Hull TD, Boddu R, Abdelmotilib HA, Mobley J, Kannarkat GT, Tansey MG, West AB. The G2019S LRRK2 mutation increases myeloid cell chemotactic responses and enhances LRRK2 binding to actin-regulatory proteins. Hum Mol Genet. 2015 Aug 1;24(15):4250-67. Epub 2015 Apr 29 PubMed.
5. Volpicelli-Daley LA, Abdelmotilib H, Liu Z, Stoyka L, Daher JP, Milnerwood AJ, Unni VK, Hirst WD, Yue Z, Zhao HT, Fraser K, Kennedy RE, West AB. G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons. J Neurosci. 2016 Jul 13;36(28):7415-27. PubMed. Correction.
6. Park J, Lee JW, Cooper SC, Broxmeyer HE, Cannon JR, Kim CH. Parkinson disease-associated LRRK2 G2019S transgene disrupts marrow myelopoiesis and peripheral Th17 response. J Leukoc Biol. 2017 Oct;102(4):1093-1102. Epub 2017 Jul 27 PubMed.

External Citations

1. Taconic, Cat# 10681
2. Scantox Neuro

Further Reading