Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010389 C>T
Position: (GRCh37/hg19):Chr17:44087755 C>T
dbSNP ID: rs63751273
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to CTG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10
Research Models: 10

Findings

P301L is one of the most common MAPT variants associated with frontotemporal dementia (FTD) worldwide. Clinical phenotypes vary widely but the most common features include behavioral disturbances, aphasia, cognitive impairment, and parkinsonism. 

Originally identified in a Dutch kindred (HFTD1), a U.S. kindred (FTD003) (Hutton et al., 1998), and in six French families diagnosed with FTD and parkinsonism (Dumanchin et al., 1998), the P301L mutation has since been found in more than 59 families and 234 individuals around the world (Moore et al., 2020).

Although most carriers have been diagnosed with behavioral variant FTD (bvFTD) (134/234; Moore et al., 2020), other diagnoses include semantic variant FTD (svFTD) or semantic variant primary progressive aphasia (svPPA) (e.g., Ishizuka et al., 2011; Tacik et al., 2017; Borrego-Écija et al., 2017; Rossi et al., 2022; Xu et al., 2023), progressive supranuclear palsy (PSP) (e.g., Kaat et al., 2009), right temporal variant FTD (rtvFTD) (e.g., Ulugut Erkoyun et al., 2021), nonfluent variant PPA (nfvPPA) (e.g., Shi et al., 2016), corticobasal syndrome (CBS) (e.g., Bugiani et al., 1999; Gatto et al., 2017), atypical Parkinson’s disease (PD) (e.g., Bird et al., 1999; Poorkaj et al., 2001), Alzheimer’s disease (AD) (e.g., Borrego-Écija et al., 2017), and dementia with Lewy bodies (DLB) (Moore et al., 2020). Across diagnoses, mean age at disease onset was 53 years, mean age at death 60 years, and mean disease duration 8 years (Moore et al., 2020). 

Interestingly, even within the same family, clinical phenotypes vary. For example, in one family, one carrier was diagnosed with FTD while his son was diagnosed with CBD (Bugiani et al., 1999). In another, one carrier was diagnosed with svPPA with refractory seizures, while a sibling and cousin were diagnosed with bvFTD (Tacik et al., 2017), and in yet another, three carriers received distinct diagnoses of bvFTD, AD, and svPPA (Borrego-Écija et al., 2017).

The genetic and/or environmental factors underpinning these differences remain elusive. Although some studies have suggested correlations between clinical phenotypes and genetic factors beyond the P301L mutation, including the MAPT H1/H2 haplotypes, these associations have not been confirmed (Tacik et al., 2017). More recently, a study of mouse and human brain samples indicated that the mutant protein adopts at least three different conformations and different combinations of these conformers may give rise to distinct neurological phenotypes (Daude et al., 2020). 

Many studies have reported patterns of autosomal dominant inheritance in families carrying the P301L variant and some have reported co-segregation with disease. In most cases, the ages of unaffected non-carriers are unavailable so it is uncertain if they remained healthy past the family’s mean age at onset, a pre-requisite for Alzforum’s definition of co-segregation (see Methods).

Carriers have been identified in Europe, including The Netherlands (e.g., Hutton et al., 1998, Rizzu et al., 1999; Van Sweiten et al., 1999; Rosso et al., 2003; Rademakers et al., 2004), France (e.g., Dumanchin et al., 1998, Clark 1998; Rademakers et al., 2004), Spain (e.g., Lladó et al., 2008; Ferrer et al., 2014; Borrego-Écija et al., 2017; Palencia-Madrid et al., 2019), Italy (e.g., Binetti et al., 2003), and Vienna (e.g., Ferrer et al., 2014). They have also been reported in North America (e.g., Clark et al., 1998; Bird et al., 1999; Houlden et al., 1999; Nasreddine et al., 1999; Hutton et al., 1998; Mirra et al., 1999; Poorkaj et al., 1998, Poorkaj et al., 2001; Walker et al., 2002; Adamec et al., 2002; Sobrido et al., 2003), and South America (e.g., Gatto et al., 2017). Also, carriers have been identified in Asia, including China (e.g., Shi et al., 2016; He et al., 2018; Mao et al., 2020; Cheng et al., 2022; Xu et al., 2023; Nan et al., 2024), Japan (e.g., Kodama et al., 2000; Tanaka et al., 2000; Kobayashi et al., 2002; Ishizuka et al., 2011; Miki et al., 2018; Kowalska et al., 2001), and Turkey (e.g., Guven et al., 2016).

High prevalence of P301L-associated disease in some regions may be explained by founder effects. For example, local mutation events may explain relatively high frequencies in populations in Spain and Italy (Palencia-Madrid et al., 2019), as well as in France and the Netherlands (Rademakers et al., 2004).

This variant was reported at a frequency of 0.0000054 in the gnomAD variant database, including three heterozygotes, all with European non-Finnish ancestry (gnomAD v4.1.0, April 2024). It was absent from HEX, a database of variants from people age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death (HEX, April 2024).

Neuropathology

Neuropathological examinations have revealed atrophy in several brain regions, including frontal and temporal lobes, basal ganglia, and hippocampus, with depigmentation of the substantia nigra. At the microscopic level, neuronal loss, ballooned neurons, and gliosis have been reported, with 4-repeat (4R) tau inclusions, particularly in the frontal and temporal cortices. In neurons, tau has been detected in ring-like and dot-like inclusions in the perinuclear region, as well as in cytoplasmic fibrillary aggregates and neuropil threads. In astrocytes, thorn-shaped inclusions have been reported, and in oligodendrocytes, coiled bodies (summarized in Karch et al., 2019, Table 1). 

Consistent with the variability in clinical phenotypes, heterogeneity in neuropathology has been observed (see Ghetti et al., 2015 for review). Examples of pathological features that vary across individuals include: types of neuronal and glial inclusions and their hyperphosphorylation profiles (e.g., Ferrer et al., 2014; Tacik et al., 2017; Borrego-Écija et al., 2017), the presence of mini Pick-like bodies (e.g., Nasreddine et al., 1999; Adamec et al., 2002; Ferrer et al., 2014; Borrego-Écija et al., 2017), and co-existence of multiple neurodegenerative pathologies, such as AD with FTD (e.g., Van Sweiten et al., 1999).

Brain imaging studies have also revealed heterogeneity (see Villa et al., 2024 for review). In most carriers with bvFTD, bilateral atrophy of frontal and temporal regions was observed. However, some had atrophy predominantly on the left side, one had generalized cortical atrophy, another hippocampal involvement, and another parietal atrophy. Moreover, in carriers diagnosed with svPPA, atrophy was most severe in the anterior temporal lobe, sometimes with a left-predominant asymmetry. In contrast, in a rtvFTD carrier, right-predominant atrophy of the anterior temporal pole was observed, and in a CBS carrier, bilateral symmetric putaminal hyperintense signals.

As noted above, different mixes of tau conformers have been identified in patients with different neurological phenotypes which may underlie some of the observed neuropathological heterogeneity (Daude et al., 2020).  

A few studies have examined early pathology before symptom onset. For example, a study including six asymptomatic carriers from five P301L families found hypometabolism and reduction in grey matter volume in the anterior cingulate (Clarke et al., 2021). Similarly, a study of an asymptomatic carrier identified signs of tau pathology and neurodegeneration in anterior cingulate, anterior temporal, middle/superior frontal, and fronto-insular cortex, and amygdala (Giannini et al., 2023). Moreover, a study that compared a presymptomatic versus a symptomatic carrier in a family with a svPPA phenotype, found that in the symptomatic case, neurodegeneration and tau accumulation overlapped extensively—with atrophy, hypometabolism, and tau deposition in the anterior temporal and frontal cortices with a left-predominant asymmetry—while in the presymptomatic carrier, tau pathology was more extensive than the region with hypometabolism (Xu et al., 2023).

Biological Effects

P301L occurs in a highly conserved region of the tau sequence within exon 10 and only affects the 4-repeat (4R) tau isoforms because exon 10 is spliced out of 3-repeat (3R) isoforms.

Aggregation
Isolates from human brains show selective aggregation of mutant 4R tau over 3R tau protein (Hutton et al., 1998; Rizzu et al., 2000; Miyasaka  et al., 2001). P301L inclusions are dynamic (Feb 2021 news; Croft et al., 2021) and heterogenous, varying between cell types (e.g., Mirra et al., 1999, Ferrer et al., 2014).

P301L enhances the ability to aggregate and the seeding potency of tau molecules (see Strang et al., 2019 for review), as assessed by experiments in vitro (e.g., Nacharaju et al., 1999; Barghorn et al., 2000; Combs et al., 2012) and in cultured cells (e.g., Guo and Lee, 2011; Mirbaha et al., 2015; Verheyen et al., 2015; Strang et al., 2017). In vivo experiments have also contributed to these observations, and helped shape a theory of how pathologic tau spreads through the brain by enabling prion-like templated misfolding, with aggregates passing between cells at synaptic sites, possibly via extracellular vesicles (e.g., Iba et al., 2013; Peeraer et al., 2015; Chakrakbarty et al., 2015; Stancu et al., 2015; Aug 2016 news; Fu et al., 2016; Gibbons et al., 2017; Sep 2021 news; Delpech et al., 2021; Hook et al., 2023).  

Tau P301L has limited ability to initiate aggregation, but it readily aggregates when seeded and fuels fibril elongation by disrupting a fold that normally suppresses β-sheet formation (von Bergen et al., 2001; Fischer et al., 2007; Combs et al., 2012; Strang et al., 2018; Xia et al., 2019). P301L appears to decrease the threshold for local expansion, helping expose the nearby aggregation-prone PHF6 sequence (³⁰⁶VQIVYK³¹¹) (Mirbaha et al., 2018; Chen et al., 2019). Heat, aggregation seeds, heparin, or high concentration facilitate this expansion converting tau into a seed-competent form. The P301L substitution does not appreciably increase β-structure in monomers, but rather promotes its adoption via intermolecular interactions and aggregation (Fischer et al., 2007). Indeed, using methylation to prevent cross-β sheets to form between peptides with the P301L substitution normalized protein structure (Zhou et al., 2022; Jul 2022 news).

As described in a preprint, cryo-electron microscopy analyses of a tau peptide that includes P301 and spans the junction between R2 and R3 (jR2R3) revealed that substitution of a leucine at P301 likely has at least two effects that promote 4R fibrillization (Vigers et al., 2023, Apr 2024 news). It allows H-bonding to form cross-β-sheets, and promotes de-wetting around residues 300 and 301 which enables hydrophobic contacts to form between tau molecules. Via hydrogen-bonding with G304, P301L appears to stabilize a turn that maintains intra-molecular strands in a strand-loop-strand structure that forms the fibril core.

However, there appears to be some variability in the way P301L tau molecules misfold and aggregate. Multiple conformations were found in transgenic mice expressing P301L: a prodromal structure and three distinct conformers (Daude et al., 2020). Interestingly, human carriers with different clinical phenotypes also harbored three types of conformers, two that were similar to those found in transgenic mice.

Several factors affect P301L tau misfolding and aggregation. For example, other aggregation-prone proteins involved in neurodegeneration, such as α-synuclein and Aβ, have been reported to modulate P301L aggregation (e.g., Benussi et al., 2005; Waxman and Giasson, 2011; Vasconcelos et al., 2016). In addition, as reported in a preprint, N-terminal truncation of the mutant protein, a modification that accumulates with age in transgenic mice, appeared to promote β-sheet formation within intracellular liquid droplets (Jul 2024 news; Soeda et al., 2024). Conversely, in the context of a larger tau protein—the spliced tau isoform known as "big tau"—P301L was less prone to aggregate in cultured cells and and in vivo, as described in a preprint (Chung et al., 2024). Interestingly, big tau is more abundant in brain regions that are less vulnerable to tau pathology, such as the brain stem and cerebellum. 

Microtubule dynamics

P301L decreases tau’s ability to promote microtubule assembly (Hasegawa et al., 1998; Hong et al., 1998; Dayanandan et al., 1999; Barghorn et al., 2000; DeTure et al., 2000), and may decrease microtubule binding (e.g., Hong et al., 1998; Nagiec et al., 2001; Xia et al., 2019), although some studies have reported little or no effect on the latter (e.g., DeTure et al., 2000; Barghorn et al., 2000; Vogelsberg-Ragaglia et al., 2000). A study in human iPSC-derived cortical neurons indicated P301L expression is associated with changes in microtubule post-translational modifications (Al Kabbani et al., 2024).

Additional subcellular effects
P301L appears to affect multiple cellular processes, including mitochondrial transport and function (Iovino et al., 2015; Tracy et al., 2022; Jan 2022 news), nucleocytoplasmic transport (Paonessa et al., 2019; Jan 2019 news), chromosome stability (Rossi et al., 2008), proteasome function (Myeku et al., 2015; Dec 2015 news), calcium signaling (Minaya et al., 2023), and glutamine transport (Sidoryk-Węgrzynowicz et al, 2023). In addition, the electrophysiological properties of iPSC-derived neurons matured earlier, and they developed abnormally shaped processes (Iovino et al., 2015). Synaptic dysfunction and mislocalization of mutant tau to dendritic spines in cultured hippocampal neurons has also been reported (Yu et al., 2024).

Some of these disruptions may be downstream consequences of mutant tau’s aggregation or its effects on microtubule dynamics. One study suggested altered signaling via the p25/Cdk5 kinase pathway may underlie several of P301L’s deleterious effects (Seo et al., 2017). In addition, direct interactions of mutant tau with cellular components beyond microtubules—such as mitochondrial proteins (Tracy et al., 2022; Jan 2022 news)—may also play a role.

Localization and timing of biological effects 
Brain regions and cell types affected by P301L have been examined in multiple studies. In the medial entorhinal cortex, for example, P301L pathology has been associated with loss of excitatory neurons, dysfunction of “grid cells” that control spatial navigation, and spatial memory impairment in mice (Jan 2017 news, Fu et al., 2017). Moreover, entorhinal cortical neurons that express wolframin-1 and project to hippocampal CA1 neurons have been implicated in the propagation of misfolded P310L tau and consequent disruption of hippocampal synapses and memory in mice (Sep 2021 news; Delpech et al., 2021).  Other studies in mice have pointed to P301L being associated with reductions in hippocampal GABAergic interneurons (Levenga et al., 2013) and loss of GABA receptors (Dec 2018 news; Jiang et al., 2018).

Effects on vascular and immune functions have also been reported. For example, soluble mutant tau in the synapse has been proposed to interfere with neurovascular coupling (Aug 2020 news, Park et al., 2020). Moreover, P301L may heighten immune responses by causing increased expression of adenosine A2A receptors, an alteration observed in human frontal cortex (Oct 2019 news; Carvalho et al., 2019). In addition, alterations in peripheral immune cell gene expression have been observed in human blood mononuclear cells (Sirkis et al., 2023). 

Regarding the timing of some of these alterations, an analysis of gene expression in transgenic P301L mice indicated that after neurofibrillary tangles form, immune gene expression ramps up several months later, and synaptic gene expression decreases in the late stages of disease (Jan 2015 news; Matarin et al., 2015).

P301L’s PHRED-scaled CADD score, which integrates diverse information in silico, is 34, well above the commonly used threshold of 20 for predicting deleteriousness (CADD v1.7, Apr 2024).

Research Models

Many mouse models carrying this mutation have been generated, including the widely used triple transgenic 3xTg and the single transgenic JNPL3 (see Research Models). The well-known conditional line rTg(tauP301L)4510 also carries P301L, but this model is problematic because the random insertion of the MAPT P301L transgene disrupted an endogenous mouse gene contributing to the line’s neuropathological and neurodegenerative phenotypes (Jul 2019 news; Gamache et al., 2019). 

A mouse model that incorporates many relevant genetic features of human MAPT is MAPT(H1.0*P301L)-GR, a mouse that carries the entire human MAPT gene, with the MAPTH1 haplotype replacing the corresponding mouse Mapt-containing region (Benzow et al., 2024). The human sequence also includes MAPT-AS1, a natural antisense transcript that regulates MAPT translation.

Induced pluripotent stem cells (iPSCs) are additional models that are proving particularly powerful for studying P301L-associated tauopathy (e.g., Iovino et al., 2015; Rasmussen et al., 2016; Nimsanor et al., 2016; Paonessa et al., 2019, Silva et al., 2019). Several P301L lines can be found in a collection of MAPT iPSC lines derived from patients with primary tauopathies, including genome-edited isogenic lines to control for inter-individual genetic variability (Oct 2019 news; Karch et al., 2019). Highlighting the ability of these cells to model human disease, the phenotypes of two lines were shown to correlate with the corresponding brain pathologies of their donors (Oakley et al., 2024).

Of note, P301L models are used to study, not only the primary tauopathies caused by thie mutation, but the secondary tauopathy associated with AD. Although an RNA-seq analysis of human brains identified a type of AD (type A) with a similar expression profile to that of P301L mouse brains, the transcriptomic profile of brains with classic AD pathology (type C) was different (Jan 2021 news, Neff et al., 2021).  Also, at least one structural study of tau aggregates suggests P301L tau may be suboptimal for modeling AD (Vigers et al., 2023).

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References

Research Models Citations

1. 3xTg
2. JNPL3(P301L)
3. rTg(tauP301L)4510
4. MAPT(H1.0*)P301L-GR

News Citations

1. Gene Disruption Haunts Tau Mouse—Knock-Ins Look Promising 16 Jul 2019
2. Introducing: iPSC Collection from Tauopathy Patients 23 Oct 2019
3. Expression Analysis Uncovers Three Distinct Forms of Alzheimer’s 14 Jan 2021
4. Not Merely Tau Tombstones, Neurofibrillary Tangles Are Dynamic 13 Feb 2021
5. No Special Glasses Needed: Three-Dimensional Views of Tau and Aβ in the Brain 3 Aug 2016
6. Wolframin-1 Cells: Tau’s Launch Pad from Entorhinal Cortex to Hippocampus? 17 Sep 2021
7. Too Clingy: Extra Hydrogen Bond Prompts Protein Aggregation 7 Jul 2022
8. Tau Toggling Peptides: One Seeds Fibrils; the Other Dismantles Them 19 Apr 2024
9. Survey of Tau Partners Highlights Synaptic, Mitochondrial Roles 27 Jan 2022
10. Invasion of the Microtubules: Mutant Tau Deforms Neuronal Nuclei 19 Jan 2019
11. Protecting Proteasomes from Toxic Tau Keeps Mice Sharp 24 Dec 2015
12. Led Astray: Pathology Tied to “Grid Cell” Malfunction in Tauopathy Model 27 Jan 2017
13. Stem Cell Model Nails Link Between Tauopathy and GABAergic Dysfunction 21 Dec 2018
14. With Tau in Synapses, NO Neurovascular Coupling 21 Aug 2020
15. Adenosine Receptors Rev Up Immune Response, Memory Loss, in Tau Model 9 Oct 2019
16. Network Analysis Points to Distinct Effects of Amyloid, Tau 25 Jan 2015

Book page Citations

1. Methods 6 Feb 2018

Paper Citations

1. Gamache J, Benzow K, Forster C, Kemper L, Hlynialuk C, Furrow E, Ashe KH, Koob MD. Factors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice. Nat Commun. 2019 Jun 6;10(1):2479. PubMed.
2. Benzow K, Karanjeet K, Oblak AL, Carter GW, Sasner M, Koob MD. Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice. Alzheimers Dement. 2024 Apr;20(4):3080-3087. Epub 2024 Feb 11 PubMed.
3. Iovino M, Agathou S, González-Rueda A, Del Castillo Velasco-Herrera M, Borroni B, Alberici A, Lynch T, O'Dowd S, Geti I, Gaffney D, Vallier L, Paulsen O, Káradóttir RT, Spillantini MG. Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain. 2015 Nov;138(Pt 11):3345-59. Epub 2015 Jul 27 PubMed.
4. Rasmussen MA, Hjermind LE, Hasholt LF, Waldemar G, Nielsen JE, Clausen C, Hyttel P, Holst B. Induced pluripotent stem cells (iPSCs) derived from a patient with frontotemporal dementia caused by a P301L mutation in microtubule-associated protein tau (MAPT). Stem Cell Res. 2016 Jan;16(1):70-4. Epub 2015 Dec 12 PubMed.
5. Nimsanor N, Kitiyanant N, Poulsen U, Rasmussen MA, Clausen C, Mau-Holzmann UA, Nielsen JE, Nielsen TT, Hyttel P, Holst B, Schmid B. Generation of an isogenic, gene-corrected iPSC line from a symptomatic 57-year-old female patient with frontotemporal dementia caused by a P301L mutation in the microtubule associated protein tau (MAPT) gene. Stem Cell Res. 2016 Nov;17(3):556-559. Epub 2016 Sep 28 PubMed.
6. Paonessa F, Evans LD, Solanki R, Larrieu D, Wray S, Hardy J, Jackson SP, Livesey FJ. Microtubules Deform the Nuclear Membrane and Disrupt Nucleocytoplasmic Transport in Tau-Mediated Frontotemporal Dementia. Cell Rep. 2019 Jan 15;26(3):582-593.e5. PubMed.
7. Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D, Zhang T, Huang HT, Lucente DE, Dickerson BC, Mitchison TJ, Fischer ES, Gray NS, Haggarty SJ. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. Elife. 2019 Mar 25;8 PubMed.
8. Karch CM, Kao AW, Karydas A, Onanuga K, Martinez R, Argouarch A, Wang C, Huang C, Sohn PD, Bowles KR, Spina S, Silva MC, Marsh JA, Hsu S, Pugh DA, Ghoshal N, Norton J, Huang Y, Lee SE, Seeley WW, Theofilas P, Grinberg LT, Moreno F, McIlroy K, Boeve BF, Cairns NJ, Crary JF, Haggarty SJ, Ichida JK, Kosik KS, Miller BL, Gan L, Goate AM, Temple S, Tau Consortium Stem Cell Group. A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies. Stem Cell Reports. 2019 Nov 12;13(5):939-955. Epub 2019 Oct 17 PubMed.
9. Oakley DH, Chung M, Abrha S, Hyman BT, Frosch MP. β-Amyloid species production and tau phosphorylation in iPSC-neurons with reference to neuropathologically characterized matched donor brains. J Neuropathol Exp Neurol. 2024 Jun 14; PubMed.
10. Neff RA, Wang M, Vatansever S, Guo L, Ming C, Wang Q, Wang E, Horgusluoglu-Moloch E, Song WM, Li A, Castranio EL, Tcw J, Ho L, Goate A, Fossati V, Noggle S, Gandy S, Ehrlich ME, Katsel P, Schadt E, Cai D, Brennand KJ, Haroutunian V, Zhang B. Molecular subtyping of Alzheimer's disease using RNA sequencing data reveals novel mechanisms and targets. Sci Adv. 2021 Jan;7(2) Print 2021 Jan PubMed.
11. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H, Pickering-Brown S, Chakraverty S, Isaacs A, Grover A, Hackett J, Adamson J, Lincoln S, Dickson D, Davies P, Petersen RC, Stevens M, de Graaff E, Wauters E, van Baren J, Hillebrand M, Joosse M, Kwon JM, Nowotny P, Che LK, Norton J, Morris JC, Reed LA, Trojanowski J, Basun H, Lannfelt L, Neystat M, Fahn S, Dark F, Tannenberg T, Dodd PR, Hayward N, Kwok JB, Schofield PR, Andreadis A, Snowden J, Craufurd D, Neary D, Owen F, Oostra BA, Hardy J, Goate A, van Swieten J, Mann D, Lynch T, Heutink P. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature. 1998 Jun 18;393(6686):702-5. PubMed.
12. Dumanchin C, Camuzat A, Campion D, Verpillat P, Hannequin D, Dubois B, Saugier-Veber P, Martin C, Penet C, Charbonnier F, Agid Y, Frebourg T, Brice A. Segregation of a missense mutation in the microtubule-associated protein tau gene with familial frontotemporal dementia and parkinsonism. Hum Mol Genet. 1998 Oct;7(11):1825-9. PubMed.
13. Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L, Van Deerlin VM, Warren JD, Fox NC, Rossor MN, Mead S, Bocchetta M, Boeve BF, Knopman DS, Graff-Radford NR, Forsberg LK, Rademakers R, Wszolek ZK, van Swieten JC, Jiskoot LC, Meeter LH, Dopper EG, Papma JM, Snowden JS, Saxon J, Jones M, Pickering-Brown S, Le Ber I, Camuzat A, Brice A, Caroppo P, Ghidoni R, Pievani M, Benussi L, Binetti G, Dickerson BC, Lucente D, Krivensky S, Graff C, Öijerstedt L, Fallström M, Thonberg H, Ghoshal N, Morris JC, Borroni B, Benussi A, Padovani A, Galimberti D, Scarpini E, Fumagalli GG, Mackenzie IR, Hsiung GR, Sengdy P, Boxer AL, Rosen H, Taylor JB, Synofzik M, Wilke C, Sulzer P, Hodges JR, Halliday G, Kwok J, Sanchez-Valle R, Lladó A, Borrego-Ecija S, Santana I, Almeida MR, Tábuas-Pereira M, Moreno F, Barandiaran M, Indakoetxea B, Levin J, Danek A, Rowe JB, Cope TE, Otto M, Anderl-Straub S, de Mendonça A, Maruta C, Masellis M, Black SE, Couratier P, Lautrette G, Huey ED, Sorbi S, Nacmias B, Laforce R Jr, Tremblay ML, Vandenberghe R, Damme PV, Rogalski EJ, Weintraub S, Gerhard A, Onyike CU, Ducharme S, Papageorgiou SG, Ng AS, Brodtmann A, Finger E, Guerreiro R, Bras J, Rohrer JD, FTD Prevention Initiative. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020 Feb;19(2):145-156. Epub 2019 Dec 3 PubMed.
14. Ishizuka T, Nakamura M, Ichiba M, Sano A. Familial semantic dementia with P301L mutation in the Tau gene. Dement Geriatr Cogn Disord. 2011;31(5):334-40. Epub 2011 May 10 PubMed.
15. Tacik P, Sanchez-Contreras M, DeTure M, Murray ME, Rademakers R, Ross OA, Wszolek ZK, Parisi JE, Knopman DS, Petersen RC, Dickson DW. Clinicopathologic heterogeneity in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) due to microtubule-associated protein tau (MAPT) p.P301L mutation, including a patient with globular glial tauopathy. Neuropathol Appl Neurobiol. 2017 Apr;43(3):200-214. Epub 2017 Mar 8 PubMed.
16. Borrego-Écija S, Morgado J, Palencia-Madrid L, Grau-Rivera O, Reñé R, Hernández I, Almenar C, Balasa M, Antonell A, Molinuevo JL, Lladó A, Martínez de Pancorbo M, Gelpi E, Sánchez-Valle R. Frontotemporal Dementia Caused by the P301L Mutation in the MAPT Gene: Clinicopathological Features of 13 Cases from the Same Geographical Origin in Barcelona, Spain. Dement Geriatr Cogn Disord. 2017;44(3-4):213-221. Epub 2017 Sep 22 PubMed.
17. Rossi G, Salvi E, Mehmeti E, Ricci M, Villa C, Prioni S, Moda F, Di Fede G, Tiraboschi P, Redaelli V, Coppola C, Koch G, Canu E, Filippi M, Agosta F, Giaccone G, Caroppo P. Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort. Front Aging Neurosci. 2022;14:1085406. Epub 2022 Dec 8 PubMed.
18. Xu J, Xia Y, Meng M, Liu F, Che P, Zhang Y, Wang Y, Cai L, Qin W, Zhang N. Clinical features and biomarkers of semantic variant primary progressive aphasia with MAPT mutation. Alzheimers Res Ther. 2023 Jan 27;15(1):21. PubMed.
20. Ulugut Erkoyun H, van der Lee SJ, Nijmeijer B, van Spaendonk R, Nelissen A, Scarioni M, Dijkstra A, Samancı B, Gürvit H, Yıldırım Z, Tepgeç F, Bilgic B, Barkhof F, Rozemuller A, van der Flier WM, Scheltens P, Cohn-Hokke P, Pijnenburg Y. The Right Temporal Variant of Frontotemporal Dementia Is Not Genetically Sporadic: A Case Series. J Alzheimers Dis. 2021;79(3):1195-1201. PubMed.
21. Shi Z, Liu S, Xiang L, Wang Y, Liu M, Liu S, Han T, Zhou Y, Wang J, Cai L, Gao S, Ji Y. Frontotemporal dementia-related gene mutations in clinical dementia patients from a Chinese population. J Hum Genet. 2016 Dec;61(12):1003-1008. Epub 2016 Jul 21 PubMed.
22. Bugiani O, Murrell JR, Giaccone G, Hasegawa M, Ghigo G, Tabaton M, Morbin M, Primavera A, Carella F, Solaro C, Grisoli M, Savoiardo M, Spillantini MG, Tagliavini F, Goedert M, Ghetti B. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol. 1999 Jun;58(6):667-77. PubMed.
23. Gatto EM, Allegri RF, Da Prat G, Chrem Mendez P, Hanna DS, Dorschner MO, Surace EI, Zabetian CP, Mata IF. Intrafamilial variable phenotype including corticobasal syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America. Neurobiol Aging. 2017 May;53:195.e11-195.e17. Epub 2017 Feb 10 PubMed.
24. Bird TD, Nochlin D, Poorkaj P, Cherrier M, Kaye J, Payami H, Peskind E, Lampe TH, Nemens E, Boyer PJ, Schellenberg GD. A clinical pathological comparison of three families with frontotemporal dementia and identical mutations in the tau gene (P301L). Brain. 1999 Apr;122 ( Pt 4):741-56. PubMed.
25. Poorkaj P, Grossman M, Steinbart E, Payami H, Sadovnick A, Nochlin D, Tabira T, Trojanowski JQ, Borson S, Galasko D, Reich S, Quinn B, Schellenberg G, Bird TD. Frequency of tau gene mutations in familial and sporadic cases of non-Alzheimer dementia. Arch Neurol. 2001 Mar;58(3):383-7. PubMed.
26. Daude N, Kim C, Kang SG, Eskandari-Sedighi G, Haldiman T, Yang J, Fleck SC, Gomez-Cardona E, Han ZZ, Borrego-Ecija S, Wohlgemuth S, Julien O, Wille H, Molina-Porcel L, Gelpi E, Safar JG, Westaway D. Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT-P301L mutation. Acta Neuropathol. 2020 Jun;139(6):1045-1070. Epub 2020 Mar 26 PubMed. Correction.
27. Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, Niermeijer MF, Hillebrand M, Ravid R, Oostra BA, Goedert M, van Duijn CM, Heutink P. High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet. 1999 Feb;64(2):414-21. PubMed.
28. van Swieten JC, Stevens M, Rosso SM, Rizzu P, Joosse M, de Koning I, Kamphorst W, Ravid R, Spillantini MG, Niermeijer, Heutink P. Phenotypic variation in hereditary frontotemporal dementia with tau mutations. Ann Neurol. 1999 Oct;46(4):617-26. PubMed.
29. Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn CM, Heutink P, van Swieten JC. Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain. 2003 Sep;126(Pt 9):2016-22. Epub 2003 Jul 22 PubMed.
30. Rademakers R, Cruts M, van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat. 2004 Oct;24(4):277-95. PubMed.
31. Clark LN, Poorkaj P, Wszolek Z, Geschwind DH, Nasreddine ZS, Miller B, Li D, Payami H, Awert F, Markopoulou K, Andreadis A, D'Souza I, Lee VM, Reed L, Trojanowski JQ, Zhukareva V, Bird T, Schellenberg G, Wilhelmsen KC. Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13103-7. PubMed.
32. Lladó A, Sánchez-Valle R, Rey MJ, Ezquerra M, Tolosa E, Ferrer I, Molinuevo JL, Catalan collaborative Study Group for FTLD. Clinicopathological and genetic correlates of frontotemporal lobar degeneration and corticobasal degeneration. J Neurol. 2008 Apr;255(4):488-94. Epub 2008 Mar 25 PubMed.
33. Ferrer I, López-González I, Carmona M, Arregui L, Dalfó E, Torrejón-Escribano B, Diehl R, Kovacs GG. Glial and neuronal tau pathology in tauopathies: characterization of disease-specific phenotypes and tau pathology progression. J Neuropathol Exp Neurol. 2014 Jan;73(1):81-97. PubMed.
34. Palencia-Madrid L, Sánchez-Valle R, Fernández de Retana I, Borrego S, Grau-Rivera O, Reñé R, Hernández I, Almenar C, Rossi G, Caroppo P, Redaelli V, Le Ber I, Camuzat A, Brice A, Antonell A, Balasa M, Gelpi E, Lladó A, de Pancorbo MM. A unique common ancestor introduced P301L mutation in MAPT gene in frontotemporal dementia patients from Barcelona (Baix Llobregat, Spain). Neurobiol Aging. 2019 Dec;84:236.e9-236.e15. Epub 2019 Aug 21 PubMed.
35. Binetti G, Nicosia F, Benussi L, Ghidoni R, Feudatari E, Barbiero L, Signorini S, Villa A, Mattioli F, Zanetti O, Alberici A. Prevalence of TAU mutations in an Italian clinical series of familial frontotemporal patients. Neurosci Lett. 2003 Feb 20;338(1):85-7. PubMed.
36. Houlden H, Baker M, Adamson J, Grover A, Waring S, Dickson D, Lynch T, Boeve B, Petersen RC, Pickering-Brown S, Owen F, Neary D, Craufurd D, Snowden J, Mann D, Hutton M. Frequency of tau mutations in three series of non-Alzheimer's degenerative dementia. Ann Neurol. 1999 Aug;46(2):243-8. PubMed.
37. Nasreddine ZS, Loginov M, Clark LN, Lamarche J, Miller BL, Lamontagne A, Zhukareva V, Lee VM, Wilhelmsen KC, Geschwind DH. From genotype to phenotype: a clinical pathological, and biochemical investigation of frontotemporal dementia and parkinsonism (FTDP-17) caused by the P301L tau mutation. Ann Neurol. 1999 Jun;45(6):704-15. PubMed.
38. Mirra SS, Murrell JR, Gearing M, Spillantini MG, Goedert M, Crowther RA, Levey AI, Jones R, Green J, Shoffner JM, Wainer BH, Schmidt ML, Trojanowski JQ, Ghetti B. Tau pathology in a family with dementia and a P301L mutation in tau. J Neuropathol Exp Neurol. 1999 Apr;58(4):335-45. PubMed.
39. Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun;43(6):815-25. PubMed.
40. Walker RH, Friedman J, Wiener J, Hobler R, Gwinn-Hardy K, Adam A, DeWolfe J, Gibbs R, Baker M, Farrer M, Hutton M, Hardy J. A family with a tau P301L mutation presenting with parkinsonism. Parkinsonism Relat Disord. 2002 Dec;9(2):121-3. PubMed.
41. Adamec E, Murrell JR, Takao M, Hobbs W, Nixon RA, Ghetti B, Vonsattel JP. P301L tauopathy: confocal immunofluorescence study of perinuclear aggregation of the mutated protein. J Neurol Sci. 2002 Aug 15;200(1-2):85-93. PubMed.
42. Sobrido MJ, Miller BL, Havlioglu N, Zhukareva V, Jiang Z, Nasreddine ZS, Lee VM, Chow TW, Wilhelmsen KC, Cummings JL, Wu JY, Geschwind DH. Novel tau polymorphisms, tau haplotypes, and splicing in familial and sporadic frontotemporal dementia. Arch Neurol. 2003 May;60(5):698-702. PubMed.
43. He S, Chen S, Xia MR, Sun ZK, Huang Y, Zhang JW. The role of MAPT gene in Chinese dementia patients: a P301L pedigree study and brief literature review. Neuropsychiatr Dis Treat. 2018;14:1627-1633. Epub 2018 Jun 18 PubMed.
44. Mao C, Dong L, Li J, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Cui L, Gao J. Phenotype Heterogeneity and Genotype Correlation of MAPT Mutations in a Chinese PUMCH Cohort. J Mol Neurosci. 2021 May;71(5):1015-1022. Epub 2020 Oct 1 PubMed.
45. Cheng HR, Lin RR, Li HL, Xue YY, Gao PR, Chen DF, Tao QQ, Wu ZY. Identification and functional characterization of novel variants of MAPT and GRN in Chinese patients with frontotemporal dementia. Neurobiol Aging. 2023 Mar;123:233-243. Epub 2022 Dec 24 PubMed.
46. Nan H, Kim YJ, Chu M, Li D, Li J, Jiang D, Wu Y, Ohtsuka T, Wu L. Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations. Alzheimers Res Ther. 2024 Jun 13;16(1):127. PubMed.
47. Kodama K, Okada S, Iseki E, Kowalska A, Tabira T, Hosoi N, Yamanouchi N, Noda S, Komatsu N, Nakazato M, Kumakiri C, Yazaki M, Sato T. Familial frontotemporal dementia with a P301L tau mutation in Japan. J Neurol Sci. 2000 May 1;176(1):57-64. PubMed.
48. Tanaka R, Kobayashi T, Motoi Y, Anno M, Mizuno Y, Mori H. A case of frontotemporal dementia with tau P301L mutation in the Far East. J Neurol. 2000 Sep;247(9):705-7. PubMed.
49. Kobayashi T, Mori H, Okuma Y, Dickson DW, Cookson N, Tsuboi Y, Motoi Y, Tanaka R, Miyashita N, Anno M, Narabayashi H, Mizuno Y. Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17. J Neurol. 2002 Jun;249(6):669-75. PubMed.
50. Miki T, Yokota O, Takenoshita S, Mori Y, Yamazaki K, Ozaki Y, Ueno SI, Haraguchi T, Ishizu H, Kuroda S, Terada S, Yamada N. Frontotemporal lobar degeneration due to P301L tau mutation showing apathy and severe frontal atrophy but lacking other behavioral changes: A case report and literature review. Neuropathology. 2018 Jun;38(3):268-280. Epub 2017 Nov 6 PubMed.
51. Kowalska A, Asada T, Arima K, Kumakiri C, Kozubski W, Takahashi K, Tabira T. Genetic analysis in patients with familial and sporadic frontotemporal dementia: two tau mutations in only familial cases and no association with apolipoprotein epsilon4. Dement Geriatr Cogn Disord. 2001;12(6):387-92. PubMed.
52. Guven G, Lohmann E, Bras J, Gibbs JR, Gurvit H, Bilgic B, Hanagasi H, Rizzu P, Heutink P, Emre M, Erginel-Unaltuna N, Just W, Hardy J, Singleton A, Guerreiro R. Mutation Frequency of the Major Frontotemporal Dementia Genes, MAPT, GRN and C9ORF72 in a Turkish Cohort of Dementia Patients. PLoS One. 2016;11(9):e0162592. Epub 2016 Sep 15 PubMed.
53. Ghetti B, Oblak AL, Boeve BF, Johnson KA, Dickerson BC, Goedert M. Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging. Neuropathol Appl Neurobiol. 2015 Feb;41(1):24-46. PubMed.
54. Villa C, Pellencin E, Romeo A, Giaccone G, Rossi G, Prioni S, Caroppo P. Dissecting the Clinical Heterogeneity and Genotype-Phenotype Correlations of MAPT Mutations: A Systematic Review. Front Biosci (Landmark Ed). 2024 Jan 16;29(1):12. PubMed.
55. Clarke MT, St-Onge F, Beauregard JM, Bocchetta M, Todd E, Cash DM, Rohrer JD, Laforce R Jr. Early anterior cingulate involvement is seen in presymptomatic MAPT P301L mutation carriers. Alzheimers Res Ther. 2021 Feb 10;13(1):42. PubMed.
56. Giannini LA, Mol MO, Rajicic A, van Buuren R, Sarkar L, Arezoumandan S, Ohm DT, Irwin DJ, Rozemuller AJ, Netherlands Brain Bank, van Swieten JC, Seelaar H. Presymptomatic and early pathological features of MAPT-associated frontotemporal lobar degeneration. Acta Neuropathol Commun. 2023 Aug 2;11(1):126. PubMed.
57. Miyasaka T, Morishima-Kawashima M, Ravid R, Kamphorst W, Nagashima K, Ihara Y. Selective deposition of mutant tau in the FTDP-17 brain affected by the P301L mutation. J Neuropathol Exp Neurol. 2001 Sep;60(9):872-84. PubMed.
58. Croft CL, Goodwin MS, Ryu DH, Lessard CB, Tejeda G, Marrero M, Vause AR, Paterno G, Cruz PE, Lewis J, Giasson BI, Golde TE. Photodynamic studies reveal rapid formation and appreciable turnover of tau inclusions. Acta Neuropathol. 2021 Mar;141(3):359-381. Epub 2021 Jan 26 PubMed.
59. Strang KH, Golde TE, Giasson BI. MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab Invest. 2019 Jul;99(7):912-928. Epub 2019 Feb 11 PubMed.
60. Nacharaju P, Lewis J, Easson C, Yen S, Hackett J, Hutton M, Yen SH. Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett. 1999 Mar 26;447(2-3):195-9. PubMed.
61. Barghorn S, Zheng-Fischhöfer Q, Ackmann M, Biernat J, von Bergen M, Mandelkow EM, Mandelkow E. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry. 2000 Sep 26;39(38):11714-21. PubMed.
62. Combs B, Gamblin TC. FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions. Biochemistry. 2012 Oct 30;51(43):8597-607. Epub 2012 Oct 18 PubMed.
63. Guo JL, Lee VM. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem. 2011 Apr 29;286(17):15317-31. Epub 2011 Mar 3 PubMed.
64. Mirbaha H, Holmes BB, Sanders DW, Bieschke J, Diamond MI. Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation. J Biol Chem. 2015 Jun 12;290(24):14893-903. Epub 2015 Apr 17 PubMed.
65. Verheyen A, Diels A, Dijkmans J, Oyelami T, Meneghello G, Mertens L, Versweyveld S, Borgers M, Buist A, Peeters P, Cik M. Using Human iPSC-Derived Neurons to Model TAU Aggregation. PLoS One. 2015;10(12):e0146127. Epub 2015 Dec 31 PubMed.
66. Strang KH, Croft CL, Sorrentino ZA, Chakrabarty P, Golde TE, Giasson BI. Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies. J Biol Chem. 2018 Feb 16;293(7):2408-2421. Epub 2017 Dec 19 PubMed.
67. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci. 2013 Jan 16;33(3):1024-37. PubMed. Correction.
68. Peeraer E, Bottelbergs A, Van Kolen K, Stancu IC, Vasconcelos B, Mahieu M, Duytschaever H, Ver Donck L, Torremans A, Sluydts E, Van Acker N, Kemp JA, Mercken M, Brunden KR, Trojanowski JQ, Dewachter I, Lee VM, Moechars D. Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice. Neurobiol Dis. 2015 Jan;73:83-95. Epub 2014 Sep 16 PubMed.
69. Chakrabarty P, Hudson VJ III, Sacino AN, Brooks MM, D'Alton S, Lewis J, Golde TE, Giasson BI. Inefficient induction and spread of seeded tau pathology in P301L mouse model of tauopathy suggests inherent physiological barriers to transmission. Acta Neuropathol. 2015 Aug;130(2):303-5. Epub 2015 May 16 PubMed.
70. Stancu IC, Vasconcelos B, Ris L, Wang P, Villers A, Peeraer E, Buist A, Terwel D, Baatsen P, Oyelami T, Pierrot N, Casteels C, Bormans G, Kienlen-Campard P, Octave JN, Moechars D, Dewachter I. Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice. Acta Neuropathol. 2015 Jun;129(6):875-94. Epub 2015 Apr 11 PubMed.
71. Fu H, Hussaini SA, Wegmann S, Profaci C, Daniels JD, Herman M, Emrani S, Figueroa HY, Hyman BT, Davies P, Duff KE. 3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice. PLoS One. 2016;11(7):e0159463. Epub 2016 Jul 28 PubMed.
72. Gibbons GS, Banks RA, Kim B, Xu H, Changolkar L, Leight SN, Riddle DM, Li C, Gathagan RJ, Brown HJ, Zhang B, Trojanowski JQ, Lee VM. GFP-Mutant Human Tau Transgenic Mice Develop Tauopathy Following CNS Injections of Alzheimer's Brain-Derived Pathological Tau or Synthetic Mutant Human Tau Fibrils. J Neurosci. 2017 Nov 22;37(47):11485-11494. Epub 2017 Oct 6 PubMed.
73. Delpech JC, Pathak D, Varghese M, Kalavai SV, Hays EC, Hof PR, Johnson WE, Ikezu S, Medalla M, Luebke JI, Ikezu T. Wolframin-1-expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory in mice. Sci Transl Med. 2021 Sep 15;13(611):eabe8455. PubMed.
74. Hook V, Podvin S, Mosier C, Boyarko B, Seyffert L, Stringer H, Rissman RA. Emerging evidence for dysregulated proteome cargoes of tau-propagating extracellular vesicles driven by familial mutations of tau and presenilin. Extracell Vesicles Circ Nucl Acids. 2023;4(4):588-598. Epub 2023 Nov 21 PubMed.
75. von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM, Mandelkow E. Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J Biol Chem. 2001 Dec 21;276(51):48165-74. PubMed.
76. Fischer D, Mukrasch MD, von Bergen M, Klos-Witkowska A, Biernat J, Griesinger C, Mandelkow E, Zweckstetter M. Structural and microtubule binding properties of tau mutants of frontotemporal dementias. Biochemistry. 2007 Mar 13;46(10):2574-82. PubMed.
77. Xia Y, Sorrentino ZA, Kim JD, Strang KH, Riffe CJ, Giasson BI. Impaired tau-microtubule interactions are prevalent among pathogenic tau variants arising from missense mutations. J Biol Chem. 2019 Nov 29;294(48):18488-18503. Epub 2019 Oct 24 PubMed.
78. Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X, Goodarzi M, Pappu RV, Colby DW, Mirzaei H, Joachimiak LA, Diamond MI. Inert and seed-competent tau monomers suggest structural origins of aggregation. Elife. 2018 Jul 10;7 PubMed.
79. Chen D, Drombosky KW, Hou Z, Sari L, Kashmer OM, Ryder BD, Perez VA, Woodard DR, Lin MM, Diamond MI, Joachimiak LA. Tau local structure shields an amyloid-forming motif and controls aggregation propensity. Nat Commun. 2019 Jun 7;10(1):2493. PubMed.
80. Zhou X, Sumrow L, Tashiro K, Sutherland L, Liu D, Qin T, Kato M, Liszczak G, McKnight SL. Mutations linked to neurological disease enhance self-association of low-complexity protein sequences. Science. 2022 Jul;377(6601):eabn5582. PubMed.
81. Vigers M, Lobo S, Najafi S, Dubose A, Tsay K, Ganguly P, Longhini AP, Jin Y, Buratto SK, Kosik KS, Shell MS, Shea J-E, Han S. Tau P301L mutation promotes core 4R tauopathy fibril fold through near-surface water structuring and conformational rearrangement. 2023 Nov 28 10.1101/2023.11.28.568818 (version 1) bioRxiv.
82. Benussi L, Ghidoni R, Paterlini A, Nicosia F, Alberici AC, Signorini S, Barbiero L, Binetti G. Interaction between tau and alpha-synuclein proteins is impaired in the presence of P301L tau mutation. Exp Cell Res. 2005 Aug 1;308(1):78-84. PubMed.
83. Waxman EA, Giasson BI. Induction of intracellular tau aggregation is promoted by α-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. J Neurosci. 2011 May 25;31(21):7604-18. PubMed.
84. Soeda Y, Yoshimura H, Bannai H, Koike R, Takashima A. Intracellular Tau Fragment Droplets Serve as Seeds for Tau Fibrils. 2023 Sep 11 10.1101/2023.09.10.557018 (version 1) bioRxiv.
85. Chung D-e, Deng X, Yalamanchili HK, Revelli J-P, Han AL, Tadros B, Richman R, Dias M, AlaviNaini F, Boeynaems S, Hyman BT, Zoghbi HY. The big tau splice isoform resists Alzheimer's-related pathological changes. 2024 Jul 31 10.1101/2024.07.30.605685 (version 1) bioRxiv.
86. Hasegawa M, Smith MJ, Goedert M. Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett. 1998 Oct 23;437(3):207-10. PubMed.
87. Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A, Morris JC, Wilhelmsen KC, Schellenberg GD, Trojanowski JQ, Lee VM. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science. 1998 Dec 4;282(5395):1914-7. PubMed.
88. Dayanandan R, Van Slegtenhorst M, Mack TG, Ko L, Yen SH, Leroy K, Brion JP, Anderton BH, Hutton M, Lovestone S. Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation. FEBS Lett. 1999 Mar 12;446(2-3):228-32. PubMed.
89. DeTure M, Ko LW, Yen S, Nacharaju P, Easson C, Lewis J, van Slegtenhorst M, Hutton M, Yen SH. Missense tau mutations identified in FTDP-17 have a small effect on tau-microtubule interactions. Brain Res. 2000 Jan 17;853(1):5-14. PubMed.
90. Nagiec EW, Sampson KE, Abraham I. Mutated tau binds less avidly to microtubules than wildtype tau in living cells. J Neurosci Res. 2001 Feb 1;63(3):268-75. PubMed.
91. Vogelsberg-Ragaglia V, Bruce J, Richter-Landsberg C, Zhang B, Hong M, Trojanowski JQ, Lee VM. Distinct FTDP-17 missense mutations in tau produce tau aggregates and other pathological phenotypes in transfected CHO cells. Mol Biol Cell. 2000 Dec;11(12):4093-104. PubMed.
92. Al Kabbani MA, Köhler C, Zempel H. Effects of P301L-TAU on post-translational modifications of microtubules in human iPSC-derived cortical neurons and TAU transgenic mice. Neural Regen Res. 2024 Jun 26; PubMed.
93. Tracy TE, Madero-Pérez J, Swaney DL, Chang TS, Moritz M, Konrad C, Ward ME, Stevenson E, Hüttenhain R, Kauwe G, Mercedes M, Sweetland-Martin L, Chen X, Mok SA, Wong MY, Telpoukhovskaia M, Min SW, Wang C, Sohn PD, Martin J, Zhou Y, Luo W, Trojanowski JQ, Lee VM, Gong S, Manfredi G, Coppola G, Krogan NJ, Geschwind DH, Gan L. Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell. 2022 Feb 17;185(4):712-728.e14. Epub 2022 Jan 20 PubMed.
94. Rossi G, Dalprà L, Crosti F, Lissoni S, Sciacca FL, Catania M, Di Fede G, Mangieri M, Giaccone G, Croci D, Tagliavini F. A new function of microtubule-associated protein tau: involvement in chromosome stability. Cell Cycle. 2008 Jun 15;7(12):1788-94. Epub 2008 Jun 25 PubMed.
95. Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE. Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling. Nat Med. 2016 Jan;22(1):46-53. Epub 2015 Dec 21 PubMed.
96. Minaya MA, Mahali S, Iyer AK, Eteleeb AM, Martinez R, Huang G, Budde J, Temple S, Nana AL, Seeley WW, Spina S, Grinberg LT, Harari O, Karch CM. Conserved gene signatures shared among MAPT mutations reveal defects in calcium signaling. Front Mol Biosci. 2023;10:1051494. Epub 2023 Feb 9 PubMed.
97. Sidoryk-Węgrzynowicz M, Dąbrowska-Bouta B, Sulkowski G, Strużyńska L. Mutant Tau protein-induced abnormalities in the Na+-dependent glutamine translocation and recycling and their impact on astrocyte-neuron integrity in vitro. Neurochem Int. 2023 Sep;168:105551. Epub 2023 Jun 7 PubMed.
98. Yu K, Yao KR, Aguinaga MA, Choquette JM, Liu C, Wang Y, Liao D. G272V and P301L Mutations Induce Isoform Specific Tau Mislocalization to Dendritic Spines and Synaptic Dysfunctions in Cellular Models of 3R and 4R Tau Frontotemporal Dementia. J Neurosci. 2024 Jul 10;44(28) PubMed.
99. Seo J, Kritskiy O, Watson LA, Barker SJ, Dey D, Raja WK, Lin YT, Ko T, Cho S, Penney J, Silva MC, Sheridan SD, Lucente D, Gusella JF, Dickerson BC, Haggarty SJ, Tsai LH. Inhibition of p25/Cdk5 Attenuates Tauopathy in Mouse and iPSC Models of Frontotemporal Dementia. J Neurosci. 2017 Oct 11;37(41):9917-9924. Epub 2017 Sep 14 PubMed.
100. Fu H, Rodriguez GA, Herman M, Emrani S, Nahmani E, Barrett G, Figueroa HY, Goldberg E, Hussaini SA, Duff KE. Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease. Neuron. 2017 Feb 8;93(3):533-541.e5. Epub 2017 Jan 19 PubMed.
101. Levenga J, Krishnamurthy P, Rajamohamedsait H, Wong H, Franke TF, Cain P, Sigurdsson EM, Hoeffer CA. Tau pathology induces loss of GABAergic interneurons leading to altered synaptic plasticity and behavioral impairments. Acta Neuropathol Commun. 2013 Jul 11;1:34. PubMed.
102. Jiang S, Wen N, Li Z, Dube U, Del Aguila J, Budde J, Martinez R, Hsu S, Fernandez MV, Cairns NJ, Dominantly Inherited Alzheimer Network (DIAN), International FTD-Genomics Consortium (IFGC), Harari O, Cruchaga C, Karch CM. Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP. Transl Psychiatry. 2018 Dec 13;8(1):265. PubMed.
103. Park L, Hochrainer K, Hattori Y, Ahn SJ, Anfray A, Wang G, Uekawa K, Seo J, Palfini V, Blanco I, Acosta D, Eliezer D, Zhou P, Anrather J, Iadecola C. Tau induces PSD95-neuronal NOS uncoupling and neurovascular dysfunction independent of neurodegeneration. Nat Neurosci. 2020 Sep;23(9):1079-1089. Epub 2020 Aug 10 PubMed.
104. Carvalho K, Faivre E, Pietrowski MJ, Marques X, Gomez-Murcia V, Deleau A, Huin V, Hansen JN, Kozlov S, Danis C, Temido-Ferreira M, Coelho JE, Mériaux C, Eddarkaoui S, Gras SL, Dumoulin M, Cellai L, NeuroCEB Brain Bank, Landrieu I, Chern Y, Hamdane M, Buée L, Boutillier AL, Levi S, Halle A, Lopes LV, Blum D. Exacerbation of C1q dysregulation, synaptic loss and memory deficits in tau pathology linked to neuronal adenosine A2A receptor. Brain. 2019 Nov 1;142(11):3636-3654. PubMed.
105. Sirkis DW, Warly Solsberg C, Johnson TP, Bonham LW, Sturm VE, Lee SE, Rankin KP, Rosen HJ, Boxer AL, Seeley WW, Miller BL, Geier EG, Yokoyama JS. Single-cell RNA-seq reveals alterations in peripheral CX3CR1 and nonclassical monocytes in familial tauopathy. Genome Med. 2023 Jul 18;15(1):53. PubMed.
106. Matarin M, Salih DA, Yasvoina M, Cummings DM, Guelfi S, Liu W, Nahaboo Solim MA, Moens TG, Paublete RM, Ali SS, Perona M, Desai R, Smith KJ, Latcham J, Fulleylove M, Richardson JC, Hardy J, Edwards FA. A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep. 2015 Feb 3;10(4):633-44. Epub 2015 Jan 22 PubMed.

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