Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PP3
Clinical Phenotype Studied: bvFTD
Position: (GRCh38/hg38):Chr17:46018629 G>A
Position: (GRCh37/hg19):Chr17:44095995 G>A
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs63750570
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GTG to ATG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 12
Research Models: 3

Findings

This variant has been associated with the behavioral variant of frontotemporal dementia (bvFTD) with carriers showing a high degree of clinical heterogeneity. In an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature, six families, including 20 presumed carriers, were reported (Moore et al., 2020, suppl tables 5-6). Data included both confirmed mutation carriers and family members who were assumed to be carriers based on their clinical phenotype. Mean age at onset was 48.2 years  with a mean duration of disease of 14.2 years. Sixteen of the presumed carriers were diagnosed with bvFTD and four with dementia not otherwise specified.

Before MAPT was identified as a disease-causing gene, a kindred in Seattle was described with early onset dementia associated with an autosomal-dominant pattern of inheritance. The initial report described 13 affected family members over three generations with disease onset ranging from 42 to 66 years. Early symptoms included prominent antisocial, psychotic, or belligerent behavior, leading to an initial diagnosis of paranoid schizophrenia in some cases, although the diagnosis was frequently changed to probable Alzheimer's disease (AD) following dementia onset. Autopsy results of affected family members failed to confirm the AD diagnosis; instead, the authors concluded that the affected family members had a distinct disease which they designated “familial presenile dementia with neurofibrillary tangles” (Sumi et al., 1992). This disease was later categorized as FTDP-17, following the discovery of linkage to chromosome 17 (Poorkaj et al., 1997). The genetic linkage was later refined to implicate MAPT (Poorkaj et al., 1998).

In this family, a.k.a. family A, the mean age of onset was 51.5 years, mean disease duration 13.8 years, and mean age at death 66.9 years (Domoto-Reilly et al., 2017). However, there was significant variability in disease onset and progression. Indeed, one woman exhibited an unusually long disease duration of 45 years, dying at age 92, while her 67-year-old son remained asymptomatic at the time of the report, despite carrying the mutation. The woman’s symptoms included personality changes starting at around age 47, with progressive mental deterioration after age 55; after age 70 she exhibited repetitive behaviors and stopped talking, and after age 80 she could not walk and ate only soft foods.

Two additional U.S families were subsequently reported: “family A” (apparently distinct from Seattle family A) and "family B" (Spina et al., 2017). In "family A," the proband developed compulsions, irritability, and mental inflexibility at age 30. He later developed memory and orientation deficits. He became apathetic and developed paranoid ideations. He had a family history of dementia with behavioral abnormalities. The proband’s maternal great grandparent and maternal grandparent were affected. The proband’s mother became disinhibited in her 40s. She exhibited a slow decline in cognition and became more rigid in her behavior and thinking. She survived until age 82. Her sibling died at age 64 after having developed personality changes at age 50. A sibling of the proband also developed personality change in their late 30s. The V337M mutation was identified in the proband and in affected family members.

In "family B" from this same report, the proband became apathetic, irritable, verbally abusive, and emotionally blunted at age 55. She became mentally rigid and had difficulty recognizing faces. She experienced marked memory impairment and deficits in executive function. She also developed a postural tremor. She died at age 68. She had a family history of dementia with behavior abnormalities. Her father developed FTD at age 61 and died at age 66 of myocardial infarct. Autopsy confirmed his diagnosis. Her father’s four siblings had similar clinical symptoms with onset in their 40s and 50s. The proband’s sister was diagnosed with schizoaffective disorder in early life and later developed early onset dementia. The V337M mutation was identified in both probands from “family A” and “family B” and in their affected family members (affected members were not specified). Cosegregation with disease was not established: unaffected, non-carriers past the mean age at onset were not reported.

Beyond the US, the V337M variant was observed in a family including three affected females from a study of 261 Chinese Han patients with FTD (Nan et al., 2024). Among the three affected individuals, one female with bvFTD had an age of disease onset of 52 years.

Collectively, these reports underscore the variable clinical expression of V337M, from prolonged courses and delayed penetrance to earlier onsets and diverse behavioral profiles.

This variant was absent from the gnomAD variant database (gnomAD v4.1.0, Apr 2024).

Neuropathology

Postmortem analysis revealed neurofibrillary tangles in several regions of the neocortex, amygdala, and parahippocampal gyrus of affected carriers. The neurofibrillary tangles were composed of paired helical filaments including all six tau isoforms (Strang et al., 2019). Notably, plaques were absent (Sumi et al., 1992; Spillantini et al., 1996).

In the two outliers from Seattle family A, postmortem analysis revealed that the 92-year-old woman had atrophy of the frontotemporal and parietal cortices, with neuron loss, astrogliosis, and extensive tau deposition throughout the cerebral cortex and hippocampus (Domoto-Reilly et al., 2017). Additionally, neurofibrillary and globose tangles were observed in the hippocampus and temporal cortex. Her son, who is also a V337M carrier but remains asymptomatic, showed no signs of atrophy on MRI at the age of 64 years.

Tau conformation and phosphorylation were assessed in three individuals with the V337M mutation from Seattle family A (Qi et al., 2025; March 2025 news). Electron cryomicroscopy revealed that tau filaments from the frontal cortex of all three cases adopted the "Alzheimer fold," characterized by paired helical filaments in all individuals and straight filaments in two of the three. Additionally, western blotting of sarkosyl-insoluble tau fractions from the frontal cortex with the phosphorylation-independent BR134 antibody showed high molecular weight bands, indicating hyperphosphorylated tau. In another report, hyperphosphorylation and neurofibrillary tangle-like tau inclusions were observed in the frontoinsular and anterior cingulate cortices in a 68-year-old V337M-positive female with bvFTD (Lin et al., 2019).

Additional imaging studies also support that tau pathology associated with V337M appears similar to that seen in AD. The PET imaging ligand flortaucipir was used to evaluate AD–type tau aggregates in the temporal pole in two individuals with the V337M mutation, including one patient with bvFTD and one with FTD with parkinsonism (Jones et al., 2018). The signal was similar to that in patients with AD and higher than in clinically normal individuals. Additionally, in another study, a 66-year-old patient with bvFTD demonstrated 18F-AV-1451 uptake bilaterally in the frontal, orbitofrontal cortex and in the anterior, lateral temporal lobe (Tsai et al., 2019).

Autopsy findings from two V337M mutation carriers in “family A” and “family B” have also been reported (Spina et al., 2017). The proband's mother from “family A” showed severe atrophy in the frontal and temporal lobes, along with the CA1 region of the hippocampus and subiculum. The highest density of neurofibrillary tangles and pretangles was in the middle frontal cortex, anterior cingulate gyrus, caudate nucleus, and amygdala. There was mild neuronal loss and gliosis in the substantia nigra. Tufted tau-positive astrocytes were seen in the putamen. TDP-43 pathology was observed in the form of neuronal cytoplasmic inclusions, especially in the CA1 region of the hippocampus, dentate gyrus, subiculum, basal ganglia, and some neocortical areas. There was also neuronal loss and gliosis associated with hippocampal sclerosis. Diffuse Aβ plaques were present in the cortex and neuritic plaques were present in the CA1/subiculum, dentate gyrus, and CA4 region of the hippocampus. Amyloid angiopathy was absent as was α-synuclein pathology. The tau pathology observed in this case matched the topography of the signal in the brain of her living son as measured by PET imaging with flortaucipir.

Another case from this report, from “family B,” showed severe atrophy of the temporal pole, insula, amygdala, orbitofrontal cortex, and ventromedial striatum (Spina et al., 2017). Mild neurofibrillary tangle pathology was seen in the entorhinal cortex, CA1/subiculum, and median raphe. Pretangles were abundant in many regions of the cortex including the frontal pole, as well as the amygdala and thalamus, among other areas. All tau inclusions stained with both 3R and 4R tau antibodies. Lewy bodies and Lewy neurites were observed in the cingulate cortex, amygdala, entorhinal cortex, and substantia nigra, among other regions. Amyloid deposits were not observed, nor were TDP-43 deposits.

On MRI in a more recent study, bilateral temporal lobe atrophy was observed in a 56-year-old V337M-carrying Chinese Han patient with bvFTD who had a disease duration of 4 years (Nan et al., 2024). Additional MRI findings from three patients with bvFTD who carried the V337M alteration showed bilateral gray matter loss in the lateral temporal lobe, while the medial temporal lobe was relatively spared; loss was also observed in the frontal lobe and basal ganglia (Whitwell et al., 2009).

Together, these data suggest that V337M can drive an AD-like tauopathy marked by paired helical filaments, hyperphosphorylation, neurofibrillary tangles, and neuronal loss, while more variable features like TDP-43 or Lewy bodies, may shape distinct disease profiles across affected individuals.

Biological Effect

Tau aggregation
In most experimental systems, V337M tau has been found to increase aggregation compared to the wild-type protein tau (see Strang et al., 2019 for review), leading to the formation of tau filaments that adopt the "Alzheimer fold" (Qi et al., 2025, March 2025 news).

Early work showed that the V337M mutation accelerates aggregation of tau into filaments in recombinant proteins in vitro, as observed through electron microscopy (Nacharaju et al., 1999). Additional studies on tau aggregation kinetics, also using electron microscopy, revealed that V337M tau had a significantly shorter lag phase than control wild-type 2N4R tau, indicating faster nucleation, though extension kinetics showed no difference from wild-type tau (Chang et al., 2008). In a separate study of heparin-induced aggregation with recombinant tau, compared to wild-type, V337M was associated with higher levels of tau oligomers—key intermediates prior to filament elongation (Maeda et al., 2018). Similarly, in a heparin-induced tau aggregation assay measured by thioflavin-S fluorescence, full-length V337M tau showed a shorter half-time for forming paired helical filaments compared to wild-type tau, while K18 fragments with the V337M mutation aggregated at a rate similar to wild-type K18 (Barghorn et al., 2000). Tau oligomers were also observed at higher levels in V337M-expressing iPSC-derived neurons versus cells expressing wild-type tau, and this effect was dose-dependent, based on the copies of the V337M allele (Samelson et al., 2024 preprint, July 2023 news). Together, these findings highlight V337M’s role in hastening early tau assembly.

Hexapeptide motifs within the tau protein are important for tau aggregation and conformation, and several are found in the microtubule binding region, including the PHF6∗∗ motif (VEVKSE), which coincides with the location of V337M (Karikari et al., 2019; Karikari et al., 2020). These motifs regulate aggregation through tau-tau interactions, which facilitate a shift from a random coil to a cross β-sheet structure. The K18 fragment, which encompasses several hexapeptide motifs, was modified to express the V337M mutation in one study to evaluate tau conformation and aggregation in vitro (Karikari et al., 2019). In a heparin-induced aggregation assay, transmission electron microscopy showed that filaments produced by V337M K18 fragments were shorter than those produced by wild-type K18 fragments, although their width did not differ. This indicated that the morphology of tau aggregates can be affected by the V337M mutation. Moreover, during the aggregation incubation period, V337M K18 fragments exhibited distinct folding patterns compared to wild-type K18, as shown by unique immunostaining profiles with antibodies targeting different epitopes.

Tau aggregation has also been studied in cell and animal models. In a transgenic mouse model expressing V337M human tau, tau aggregation was observed in the hippocampus and cerebral cortex based on Congo red birefringence and thioflavin-S-positive staining, indicating neurofibrillary tangle–like histological features (Tanemura et al., 2001). Transgenic V337M mice also displayed increased accumulations of insoluble tau in lysates from the hippocampus compared to non-transgenic mice, and these lysates contained an increased amount of phosphorylated tau (Tanemura et al., 2002, Jan 2002 news). In a transgenic C. elegans model expressing V337M tau, sequential extraction revealed the presence of insoluble tau that progressively worsened with age (Kraemer et al., 2003). In contrast, human neuroglioma H4 cells transfected with V337M tau did not display thioflavin-S-positive staining, suggesting aggregates are not present and that this model is one of pretangle pathology (DeTure et al., 2002).

Tau phosphorylation
As noted above, human carriers develop hyperphosphorylated tau tangles. Similarly, transgenic mice expressing V337M human tau exhibited accumulations of phosphorylated tau as detected with antibodies PS199 and AT8 in the hippocampus (Tanemura et al., 2002, Jan 2002 news). Studies using isolated proteins and cell assays, however, reveal that V337M’s potential to increase or decrease phosphorylation depends on the system and kinase involved, indicating a nuanced balance between phosphorylation and dephosphorylation processes.

For example, an in vitro study using a recombinant system, suggested the V337M mutation enhances tau’s susceptibility to phosphorylation, with the mutant protein serving as a more favorable substrate for phosphorylation by brain protein kinases than wild-type tau (Alonso et al., 2004). This pattern was observed in another study of recombinantly expressed human tau, where Cdk5 kinase induced higher phosphorylation at S202/205 and S235 in V337M tau compared to wild-type tau, as detected by western blotting with phospho-specific antibodies, though phosphorylation levels at S396/404 and 231 remained similar between genotypes (Han et al., 2009). In contrast, when focusing on phosphorylation by glycogen synthase kinase 3β (GSK3β) in recombinant 2N4R isoform tau, no differences in general mapping patterns emerged from two dimensional phosphopeptide mapping (Connell et al., 2001).

In cellular models, V337M’s impact on tau phosphorylation appears to vary by system. In COS-7 cells transfected with V337M tau, western blotting revealed significantly increased phosphorylation at T231, but not at S396 or S409 (Yanagi et al., 2009). However, in Chinese hamster ovary (CHO) cells transfected with V337M tau, the phosphorylation pattern at key sites—S396/404, T181, S262, and T231—remained comparable to wild-type tau, as assessed by immunoblot analysis with phosphorylation-specific antibodies (Vogelsberg-Ragagliaet al., 2000). Similarly, CHO cells transfected with both GSK3β and V337M tau (3R and 4R) showed no phosphorylation differences (Dayanandan et al., 1999). Yet, in human neuroglioma H4 cells transfected with V337M tau, phosphorylation was reduced at most measured sites (T181, S202/T205, T231) compared to wild-type tau, though elevated at S396/S404 (DeTure et al., 2002).

In iPSC-derived neurons from a V337M carrier, tau phosphorylation and fragmentation were increased (Ehrlich et al., 2015). However, in a preprint, broad hypophosphorylation in V337M-carrying iPSC-derived neurons was reported. In this study using phosphoproteomics validated with western blotting, Mohl and colleagues found tau phosphorylation was markedly lower in mutant versus wild-type neurons (Mohl et al., 2024). Additional unbiased functional genomics (CRISPR) screens uncovered the p38 MAPK pathway as a likely contributor to these V337M-mediated effects.

Some studies have suggested that phosphorylation increases may stem from altered dephosphorylation. For example, one report found a reduced binding affinity of V337M tau for protein phosphatase 2A (PP2A), a major phosphatase of tau, via coimmunoprecipitation of transfected mouse NIH 3T3 fibroblasts and monkey kidney CV-1 cells (Goedert et al., 2000). In another study of HEK293 cells transfected with a V337M mutant human tau, PP2A promoted dephosphorylation at S235, T231, and S202/205, while PP2B promoted it at S202/205 (Han and Paudel 2009). 

Microtubule binding, assembly, and structure
The V337M mutation, localized to tau’s fourth microtubule-binding repeat, has variable impacts on microtubule binding, assembly, and structure, as demonstrated across experimental paradigms, but shows a tendency toward reduced microtubule formation (Strang et al., 2019). In a recombinant assay,  microtubule assembly was found to be robustly reduced compared to wild-type, using either 3R or 4R isoforms (Hasegawa et al., 1998). Similarly, a later study using light scattering found that assembly, including nucleation and polymerization, was reduced in recombinant V337M tau phosphorylated at S202 compared to wild-type tau with the same phosphorylation (Han et al., 2009). While these studies did not separate nucleation and growth rates, another recombinant analysis reported reduced nucleation with V337M (Hong et al., 1998), though a separate report found no differences in these measures (DeTure et al., 2000). Additionally, a subsequent in vitro study, using a fluorescence-based assay, indicated that while V337M tau had no significant effect on maximum microtubule polymerization, the rate of microtubule polymerization was increased, and the polymerization lag time was decreased compared to wild-type tau (Combs and Gamblin 2012). Extending to cellular context, an assay with CHO cells showed a marginally significant reduction in microtubule extension in V337M-expressing cells (Dayanandan et al., 1999). Discrepancies here may stem from differences in phosphorylation states or assay sensitivity, with phosphorylation (e.g., at S202) potentially amplifying V337M’s impact on assembly kinetics.

V337M tau also exhibits mixed effects on microtubule binding, although the trend is towards reduced binding (Strang et al., 2019). In two recombinant studies using taxol-stabilized microtubules, no differences in binding were found between mutant and wild-type tau (Barghorn et al., 2000; DeTure et al., 2000), and a study in CHO cells expressing V337M tau similarly reported no significant difference in binding to endogenous microtubules compared to cells expressing wild-type tau (Vogelsberg-Ragagliaet al., 2000). Likewise, in CHO cells with 4R V337M tau, microtubule stability following treatment with the depolymerizing agent colcemid matched that of wild-type tau (Matsumura et al., 1999). However, contrasting evidence emerged in HEK293 cells transiently transfected with V337M tau, where a higher proportion of mutant tau was found in the cytosolic versus cytoskeletal fraction compared to wild-type tau, suggesting reduced binding (Nagiec et al., 2001). This finding was reinforced by microscopy (Nagiec et al., 2001), and another recombinant study in which microtubules were stabilized with taxol (Hong et al., 1998). These inconsistencies may reflect methodological variations or cell-specific microtubule dynamics.

With regard to microtubule organization, V337M leads to disruption across diverse models. In COS-7 cells transfected with V337M human tau, confocal microscopy revealed disrupted microtubule networks (Arawaka et al., 1999). Another COS-7 study found that 3R V337M tau, but not 4R, severely altered cellular structure—showing almost no processes—and severely disturbed the microtubule network (Sahara et al., 2000). In transfected SH-SY5Y cells, V337M was associated with shorter neurites (Furukawa et al., 2003). Disruption was also observed at the ultrastructural level in SF9 insect cells transfected with V337M tau (Frappier et al., 1999). In this study, microtubules were separated by greater distances than in cells with wild-type tau, which displayed highly ordered microtubule packing. Similarly, in a knock-in Drosophila model expressing V337M tau, the cross-sectional area of microtubules in neural tissue was increased compared to control flies (Law et al., 2022). These studies suggest that V337M consistently disrupts microtubule structure across cellular environments.

Splicing
In iPSC-derived neurons, the proportion 4R tau isoform expression remained consistent between controls and those expressing V337M, contrasting with other tau mutations that disrupt splicing and increase the 4R-to-3R ratio (Ehrlich et al., 2015). This lack of change in the 4R-to-3R ratio compared to controls was also observed in frontal cortex and cerebellum extracts from patients with V337M (Hong et al., 1998).

Neuronal abnormalities
V337M drives diverse neuronal abnormalities, with reported effects on cytoskeletal integrity, cellular function, synaptic function and morphology, and lipid homeostasis, underscoring the mutation’s complex role in neuronal dysfunction. In transgenic mice expressing V337M human tau, neurons appeared irregularly shaped, with a notable loss of normal microtubules (as detected by reduced α-tubulin immunoreactivity) and RNA accumulation, features absent in non-transgenic littermates (Tanemura et al., 2002, Jan 2002 news). At the ultrastructural level, these neurons exhibited swollen Golgi networks.

Additionally, electrophysiological recordings from hippocampal slices of these mice revealed reduced neural activity, suggesting functional compromise. Similarly, in a transgenic C. elegans model expressing V337M, axonal degeneration occurred alongside impaired cholinergic transmission, highlighting both structural and functional deficits (Kraemer et al., 2003). In Drosophila V337M models, neuronal abnormalities were also present. For example, a knock-in Drosophila model displayed neuronal degeneration and axonal fragmentation (Cassar et al., 2020; Law et al., 2022). Moreover, in flies expressing V337M tau, circadian expression of end-binding protein 1 (EB1)—a key cytoskeletal regulator involved in synaptic homeostasis—was disrupted (Cassar et al., 2020). Further evidence of synaptic effects in Drosophila showed that overexpressing V337M tau led to abnormal neuromuscular junction morphology (Blard et al., 2007), and another transgenic V337M Drosophila study found reduced activity of the neurotransmitter enzymes acetylcholinesterase and butyrylcholinesterase compared to flies expressing human wild-type tau (Haddadi et al., 2016).

Moreover, a transgenic V337M mouse model revealed region-specific synaptic and glutamatergic changes (Warmus et al., 2014). Excitatory glutamatergic transmission was depressed in the ventral—but not dorsal—striatum compared to nontransgenic controls. Moreover, morphological changes and loss of glutamatergic receptors in synapses of the ventral striatum and the insular cortex, but not the dorsal striatum or motor cortex, were observed.  

In human iPSC-derived cerebral organoids carrying the V337M mutation, enhanced glutamatergic toxicity was observed, and a reduction of excitatory neurons was found at later stages of organoid development (Bowles et al., 2021). RNAseq analysis highlighted altered expression of genes tied to neuroinflammation, neurogenesis, and synaptic signaling pathways, including those encoding glutamatergic receptors. Of note, another study reported overlapping RNAseq findings in V337M iPSC-derived neurons, showing dysregulated transcripts linked to axonogenesis and axon morphology, alongside altered phosphorylation of related proteins, as confirmed by phosphoproteomic analysis (Mohl et al., 2024). In another study of cerebral organoids, single-cell RNAseq indicated that astrocytes have upregulated expression of genes in the cholesterol biosynthesis pathway (Glasauer et al., 2022; Sep 2022 news).

Other iPSC-derived models highlight additional neuronal impairments. In iPSC-derived neurons from a V337M carrier, neurite extension was disrupted compared to control cells, though somatodendritic redistribution of phosphorylated tau (which has been seen with other tau mutations) was absent (Ehrlich et al., 2015). Similarly, V337M-expressing iPSC-derived neurons had a shorter axon initial segment as well as hyperexcitability and decreased plasticity, potentially related to the tighter binding of V337M to the cytoskeletal protein EB3 in a recombinant assay compared to wild-type tau (Sep 2019 news, Sohn et al., 2019). In another report, live axon trafficking assessed in V337M patient–derived motor neurons revealed mitochondria and lysosomes traveled less distance and more slowly compared to organelles in wild-type cells (Hartmann et al., 2024). 

Calcium homeostasis has been examined in SH-SY5Y cells transfected with V337M tau (Furukawa et al., 2003). These cells showed a greater rise in intracellular calcium in response to a depolarizing stimulus (KCl), an effect mediated by L-type voltage-dependent calcium channels and possibly linked to destabilized microtubules and increased apoptosis (also see Furukawa et al., 2000).

The V337M mutation also appears to disrupt neuronal lipogenesis and lipid mobilization, with non-cell autonomous effects on glial cells leading to further dysfunction. Studies in human iPSC-derived V337M neurons revealed elevated lipid droplet accumulation, impaired lipid turnover, and increased expression of genes related to lipid droplet formation compared to wild-type controls (Li et al., 2024, Apr 2024 news). When exposed to conditioned media from these neurons, mouse microglia accumulated lipid droplets and exhibited inflammation, suggesting a neuron-to-glia lipid transfer mechanism that amplifies V337M-associated neurotoxicity.   

Proteostasis and metabolic abnormalities
V337M tau has been reported to compromise proteostasis by impairing organelle integrity, altering proteolysis, and disrupting proteasome and autophagy-lysosomal pathways, suggesting a multifaceted role in metabolic dysregulation.

For example, overexpression of V337M human tau in primary rat hippocampal neurons led to increased Golgi apparatus fragmentation compared to wild-type tau, as detected by immunofluorescence, suggesting impaired protein sorting (Liazoghli et al., 2005). Moreover, in a knock-in Drosophila model expressing V337M tau, proteostasis was compromised specifically in the cytoplasm of cells in the central nervous system (Curley et al., 2024).

In human iPSC-derived glutamatergic neurons expressing V337M tau, the interactome was altered, with reduced interactions between tau and mitochondrial proteins compared to wild-type tau, and this was associated with decreased mitochondrial membrane potential and altered respiration, including higher basal rates but lower respiratory control ratio and spare respiratory capacity (Tracy et al., 2022; Jan 2022 news).

V337M also appears to alter proteolysis. In COS-7 cells transected with V337M tau, pulse-chase experiments revealed attenuated tau proteolysis (Yanagi et al., 2009). Similarly, recombinant V337M tau showed reduced degradation compared to wild-type tau following treatment with calpain I (Yen et al., 1999). In contrast, a study of iPSC-derived neurons showed elevated caspase-mediated cleavage, which generates toxic tau fragments (Theofilas et al., 2024). These cleaved tau products, as well as caspase-6 itself, were also found in postmortem tissue from a V337M carrier. Differences between studies may be due to differential effects of specific enzymes or different experimental systems.

Proteasome dysfunction has also been reported in a study of patient-derived V337M iPSCs that were transduced with a fluorescently tagged ubiquitin reporter (D'Brant et al., 2024 preprint). Further, autophagy-lysosomal pathway dysfunction was observed on electron microscopy based on the presence of lamellar bodies, as well as on the expression of autophagy-lysosome markers in V337M mutant cerebral organoids (Bowles et al., 2021).  

Transcriptomics
Microarrays have been used to evaluate the transcriptome of iPSC-derived neurons from a patient with the V337M mutation (Ehrlich et al., 2015). Gene expression profiles were found to be altered, with 42 upregulated and 113 downregulated genes compared to control cells. Gene ontology terms for the downregulated genes included monooxygenase activity, GTPase regulator activity, and cytoskeleton organization and biogenesis.

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 (29.9), suggesting a deleterious effect (CADD v1.7, April 2024).

Pathogenicity

Frontotemporal Dementia Spectrum : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Research Models

To explore the effects of the V337M mutation, several research models have been developed, including transgenic mouse models (e.g., Tau V337M Tanemura et al., 2001; TMHT (Thy-1 mutated human tau) Flunkert et al., 2013;  Lambourne et al., 2005; Warmus et al., 2014; Chen et al., 2023), transgenic C. elegans models (Russell et al., 2021; Kraemer et al., 2003; Ferree et al., 2012; Di Domenico et al., 2012; Gamir-Morralla et al., 2019), transgenic and knock-in Drosophila models (Haddadi et al., 2016; Law et al., 2022; Pragati et al., 2020; Nisha and Sarkar 2022; Shulman and Feany 2003; Wittmann et al., 2001). A lamprey model has also been developed to overexpress V337M tau in anterior bulbar cells (Lee et al., 2009).

With regard to human cell models, several iPSC lines have been established from patients with the V337M mutation, allowing for detailed mechanistic studies at the cellular and molecular levels (Ehrlich et al., 2015; Reilly et al., 2017; Korn et al., 2023; D'Brant et al., 2024 preprint; Samelson et al., 2024 preprint; Jul 2023 news). Human iPSCs engineered to express V337M with CRISPR have also been generated (Karch et al., 2019; Oct 2019 news). iPSC-derived cerebral organoids have also been developed to examine V337M from mutant-carrying donors (Bowles et al., 2021). Human cell lines have also been used in which V337M tau is transfected, including neuroglioma cells (DeTure et al., 2002).

Lastly, to facilitate recombinant protein studies, a plasmid library has been developed containing V337M mutant full-length and K18 fragment tau, including cysteine-modified variants (Karikari et al., 2020).

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References

Research Models Citations

1. Tau V337M
2. TMHT (Thy-1 mutated human tau)

News Citations

1. CRISPR Screens Net Tau Partners in Human Neurons, Brain 21 Jul 2023
2. Introducing: iPSC Collection from Tauopathy Patients 23 Oct 2019
3. Filling in the Family Tree: AD, CTE Folds Spotted in Other Tauopathies 27 Mar 2025
4. Transgenic Mice Accumulate Human Tau in Degenerating Hippocampal Neurons 22 Nov 2002
5. Organoids Implicate Cholesterol Dysregulation in Tau Pathology 16 Sep 2022
6. Mutant Tau Stiffens Axon Cytoskeleton Near Soma 20 Sep 2019
7. Stirred by Tau, Neurons Amp Up Lipid Droplets in Glia 30 Apr 2024
8. Survey of Tau Partners Highlights Synaptic, Mitochondrial Roles 27 Jan 2022

Paper Citations

1. Tanemura K, Akagi T, Murayama M, Kikuchi N, Murayama O, Hashikawa T, Yoshiike Y, Park JM, Matsuda K, Nakao S, Sun X, Sato S, Yamaguchi H, Takashima A. Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau. Neurobiol Dis. 2001 Dec;8(6):1036-45. PubMed.
2. Flunkert S, Hierzer M, Löffler T, Rabl R, Neddens J, Duller S, Schofield EL, Ward MA, Posch M, Jungwirth H, Windisch M, Hutter-Paier B. Elevated levels of soluble total and hyperphosphorylated tau result in early behavioral deficits and distinct changes in brain pathology in a new tau transgenic mouse model. Neurodegener Dis. 2013;11(4):194-205. Epub 2012 Jul 10 PubMed.
3. Lambourne SL, Sellers LA, Bush TG, Choudhury SK, Emson PC, Suh YH, Wilkinson LS. Increased tau phosphorylation on mitogen-activated protein kinase consensus sites and cognitive decline in transgenic models for Alzheimer's disease and FTDP-17: evidence for distinct molecular processes underlying tau abnormalities. Mol Cell Biol. 2005 Jan;25(1):278-93. PubMed.
4. Warmus BA, Sekar DR, McCutchen E, Schellenberg GD, Roberts RC, McMahon LL, Roberson ED. Tau-mediated NMDA receptor impairment underlies dysfunction of a selectively vulnerable network in a mouse model of frontotemporal dementia. J Neurosci. 2014 Dec 3;34(49):16482-95. PubMed.
5. Chen L, Deng L, Sun W, Liu J, Zhang T, Li S. [Development of a tau-V337M mouse model using CRISPR/Cas9 system and enhanced ssODN-mediated recombination]. Sheng Wu Gong Cheng Xue Bao. 2023 Jul 25;39(7):3003-3014. PubMed.
6. Russell JC, Lei H, Chaliparambil RK, Fish S, Markiewicz SM, Lee TI, Noori A, Kaeberlein M. Generation and characterization of a tractable C. elegans model of tauopathy. Geroscience. 2021 Oct;43(5):2621-2631. Epub 2021 Sep 18 PubMed.
7. Kraemer BC, Zhang B, Leverenz JB, Thomas JH, Trojanowski JQ, Schellenberg GD. Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9980-5. Epub 2003 Jul 18 PubMed.
8. Ferree A, Guillily M, Li H, Smith K, Takashima A, Squillace R, Weigele M, Collins JJ, Wolozin B. Regulation of physiologic actions of LRRK2: focus on autophagy. Neurodegener Dis. 2012;10(1-4):238-41. Epub 2011 Dec 23 PubMed.
9. Di Domenico F, Sultana R, Ferree A, Smith K, Barone E, Perluigi M, Coccia R, Pierce W, Cai J, Mancuso C, Squillace R, Wiengele M, Dalle-Donne I, Wolozin B, Butterfield DA. Redox proteomics analyses of the influence of co-expression of wild-type or mutated LRRK2 and Tau on C. elegans protein expression and oxidative modification: relevance to Parkinson disease. Antioxid Redox Signal. 2012 Dec 1;17(11):1490-506. Epub 2012 Mar 20 PubMed.
10. Gamir-Morralla A, Sacristán S, Medina M, Iglesias T. Effects of Thioflavin T and GSK-3 Inhibition on Lifespan and Motility in a Caenorhabditis elegans Model of Tauopathy. J Alzheimers Dis Rep. 2019 Feb 16;3(1):47-57. PubMed.
11. Haddadi M, Nongthomba U, Ramesh SR. Biochemical and Behavioral Evaluation of Human MAPT Mutations in Transgenic Drosophila melanogaster. Biochem Genet. 2016 Feb;54(1):61-72. Epub 2015 Nov 18 PubMed.
12. Law AD, Cassar M, Long DM, Chow ES, Giebultowicz JM, Venkataramanan A, Strauss R, Kretzschmar D. FTD-associated mutations in Tau result in a combination of dominant and recessive phenotypes. Neurobiol Dis. 2022 Aug;170:105770. Epub 2022 May 16 PubMed.
13. Pragati, Chanu SI, Sarkar S. Reduced expression of dMyc mitigates TauV337M mediated neurotoxicity by preventing the Tau hyperphosphorylation and inducing autophagy in Drosophila. Neurosci Lett. 2020 Jan 10;715:134622. Epub 2019 Nov 9 PubMed.
14. Nisha, Sarkar S. Downregulation of glob1 mitigates human tau mediated neurotoxicity by restricting heterochromatin loss and elevating the autophagic response in drosophila. Mol Biol Rep. 2022 Jul;49(7):6581-6590. Epub 2022 May 28 PubMed.
15. Shulman JM, Feany MB. Genetic modifiers of tauopathy in Drosophila. Genetics. 2003 Nov;165(3):1233-42. PubMed.
16. Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science. 2001 Jul 27;293(5530):711-4. Epub 2001 Jun 14 PubMed.
17. Lee S, Jung C, Lee G, Hall GF. Exonic point mutations of human tau enhance its toxicity and cause characteristic changes in neuronal morphology, tau distribution and tau phosphorylation in the lamprey cellular model of tauopathy. J Alzheimers Dis. 2009;16(1):99-111. PubMed.
18. Ehrlich M, Hallmann AL, Reinhardt P, Araúzo-Bravo MJ, Korr S, Röpke A, Psathaki OE, Ehling P, Meuth SG, Oblak AL, Murrell JR, Ghetti B, Zaehres H, Schöler HR, Sterneckert J, Kuhlmann T, Hargus G. Distinct Neurodegenerative Changes in an Induced Pluripotent Stem Cell Model of Frontotemporal Dementia Linked to Mutant TAU Protein. Stem Cell Reports. 2015 Jul 14;5(1):83-96. Epub 2015 Jul 2 PubMed.
19. Reilly P, Winston CN, Baron KR, Trejo M, Rockenstein EM, Akers JC, Kfoury N, Diamond M, Masliah E, Rissman RA, Yuan SH. Novel human neuronal tau model exhibiting neurofibrillary tangles and transcellular propagation. Neurobiol Dis. 2017 Oct;106:222-234. Epub 2017 Jun 10 PubMed.
20. Korn L, Speicher AM, Schroeter CB, Gola L, Kaehne T, Engler A, Disse P, Fernández-Orth J, Csatári J, Naumann M, Seebohm G, Meuth SG, Schöler HR, Wiendl H, Kovac S, Pawlowski M. MAPT genotype-dependent mitochondrial aberration and ROS production trigger dysfunction and death in cortical neurons of patients with hereditary FTLD. Redox Biol. 2023 Feb;59:102597. Epub 2022 Dec 30 PubMed.
21. D'Brant L, Rugenstein N, Na SK, Miller MJ, Czajka TF, Trudeau N, Fitz EM, Tomaszek L, Fisher ES, Mash ES, Joy S, Lotz S, Borden S, Stevens K, Goderie S, Wang Y, Bertucci T, Karch CM, Temple S, Butler D. Fully Human Bifunctional Intrabodies Achieve Graded Reduction of Intracellular Tau and Rescue Survival of MAPT Mutation iPSC-derived Neurons. 2024 Jun 01 10.1101/2024.05.28.596248 (version 1) bioRxiv.
22. Samelson AJ, Ariqat N, McKetney J, Rohanitazangi G, ParraBravo C, Bose R, Travaglini KJ, Lam VL, Goodness D, Dixon G, Marzette E, Jin J, Tian R, Tse E, Abskharon R, Pan H, Carroll EC, Lawrence RE, Gestwicki JE, Eisenberg D, Kanaan NM, Southworth DR, Gross JD, Gan L, Swaney DL, Kampmann M. CRISPR screens in iPSC-derived neurons reveal principles of tau proteostasis. 2024 Nov 04 10.1101/2023.06.16.545386 (version 4) bioRxiv.
23. 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.
24. Bowles KR, Silva MC, Whitney K, Bertucci T, Berlind JE, Lai JD, Garza JC, Boles NC, Mahali S, Strang KH, Marsh JA, Chen C, Pugh DA, Liu Y, Gordon RE, Goderie SK, Chowdhury R, Lotz S, Lane K, Crary JF, Haggarty SJ, Karch CM, Ichida JK, Goate AM, Temple S. ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell. 2021 Aug 19;184(17):4547-4563.e17. Epub 2021 Jul 26 PubMed.
25. DeTure M, Ko LW, Easson C, Yen SH. Tau assembly in inducible transfectants expressing wild-type or FTDP-17 tau. Am J Pathol. 2002 Nov;161(5):1711-22. PubMed.
26. Karikari TK, Keeling S, Hill E, Lantero Rodrı Guez J, Nagel DA, Becker B, Höglund K, Zetterberg H, Blennow K, Hill EJ, Moffat KG. Extensive Plasmid Library to Prepare Tau Protein Variants and Study Their Functional Biochemistry. ACS Chem Neurosci. 2020 Oct 7;11(19):3117-3129. Epub 2020 Sep 16 PubMed.
27. 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.
28. Sumi SM, Bird TD, Nochlin D, Raskind MA. Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala. Neurology. 1992 Jan;42(1):120-7. PubMed.
29. 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.
30. Domoto-Reilly K, Davis MY, Keene CD, Bird TD. Unusually long duration and delayed penetrance in a family with FTD and mutation in MAPT (V337M). Am J Med Genet B Neuropsychiatr Genet. 2017 Jan;174(1):70-74. Epub 2016 Mar 16 PubMed.
31. Spina S, Schonhaut DR, Boeve BF, Seeley WW, Ossenkoppele R, O'Neil JP, Lazaris A, Rosen HJ, Boxer AL, Perry DC, Miller BL, Dickson DW, Parisi JE, Jagust WJ, Murray ME, Rabinovici GD. Frontotemporal dementia with the V337M MAPT mutation: Tau-PET and pathology correlations. Neurology. 2017 Feb 21;88(8):758-766. Epub 2017 Jan 27 PubMed.
32. 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.
33. 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.
34. Spillantini MG, Crowther RA, Goedert M. Comparison of the neurofibrillary pathology in Alzheimer's disease and familial presenile dementia with tangles. Acta Neuropathol. 1996 Jul;92(1):42-8. PubMed.
35. Qi C, Lövestam S, Murzin AG, Peak-Chew S, Franco C, Bogdani M, Latimer C, Murrell JR, Cullinane PW, Jaunmuktane Z, Bird TD, Ghetti B, Scheres SH, Goedert M. Tau filaments with the Alzheimer fold in human MAPT mutants V337M and R406W. Nat Struct Mol Biol. 2025 Jul;32(7):1297-1304. Epub 2025 Mar 5 PubMed.
36. Lin LC, Nana AL, Hepker M, Hwang JL, Gaus SE, Spina S, Cosme CG, Gan L, Grinberg LT, Geschwind DH, Coppola G, Rosen HJ, Miller BL, Seeley WW. Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants. Acta Neuropathol Commun. 2019 Oct 22;7(1):159. PubMed.
37. Jones DT, Knopman DS, Graff-Radford J, Syrjanen JA, Senjem ML, Schwarz CG, Dheel C, Wszolek Z, Rademakers R, Kantarci K, Petersen RC, Jack CR Jr, Lowe VJ, Boeve BF. In vivo 18F-AV-1451 tau PET signal in MAPT mutation carriers varies by expected tau isoforms. Neurology. 2018 Mar 13;90(11):e947-e954. Epub 2018 Feb 9 PubMed.
38. Tsai RM, Bejanin A, Lesman-Segev O, LaJoie R, Visani A, Bourakova V, O'Neil JP, Janabi M, Baker S, Lee SE, Perry DC, Bajorek L, Karydas A, Spina S, Grinberg LT, Seeley WW, Ramos EM, Coppola G, Gorno-Tempini ML, Miller BL, Rosen HJ, Jagust W, Boxer AL, Rabinovici GD. 18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes. Alzheimers Res Ther. 2019 Jan 31;11(1):13. PubMed.
39. Whitwell JL, Jack CR Jr, Boeve BF, Senjem ML, Baker M, Ivnik RJ, Knopman DS, Wszolek ZK, Petersen RC, Rademakers R, Josephs KA. Atrophy patterns in IVS10+16, IVS10+3, N279K, S305N, P301L, and V337M MAPT mutations. Neurology. 2009 Sep 29;73(13):1058-65. PubMed.
40. 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.
41. Chang E, Kim S, Yin H, Nagaraja HN, Kuret J. Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps. J Neurochem. 2008 Nov;107(4):1113-23. Epub 2008 Sep 18 PubMed.
42. Maeda S, Sato Y, Takashima A. Frontotemporal dementia with Parkinsonism linked to chromosome-17 mutations enhance tau oligomer formation. Neurobiol Aging. 2018 Sep;69:26-32. Epub 2018 May 7 PubMed.
43. 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.
44. Karikari TK, Nagel DA, Grainger A, Clarke-Bland C, Crowe J, Hill EJ, Moffat KG. Distinct Conformations, Aggregation and Cellular Internalization of Different Tau Strains. Front Cell Neurosci. 2019;13:296. Epub 2019 Jul 9 PubMed.
45. Tanemura K, Murayama M, Akagi T, Hashikawa T, Tominaga T, Ichikawa M, Yamaguchi H, Takashima A. Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci. 2002 Jan 1;22(1):133-41. PubMed.
46. Alonso Ad, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem. 2004 Aug 13;279(33):34873-81. Epub 2004 Jun 9 PubMed.
47. Han D, Qureshi HY, Lu Y, Paudel HK. Familial FTDP-17 missense mutations inhibit microtubule assembly-promoting activity of tau by increasing phosphorylation at Ser202 in vitro. J Biol Chem. 2009 May 15;284(20):13422-13433. Epub 2009 Mar 19 PubMed.
48. Connell JW, Gibb GM, Betts JC, Blackstock WP, Gallo J, Lovestone S, Hutton M, Anderton BH. Effects of FTDP-17 mutations on the in vitro phosphorylation of tau by glycogen synthase kinase 3beta identified by mass spectrometry demonstrate certain mutations exert long-range conformational changes. FEBS Lett. 2001 Mar 23;493(1):40-4. PubMed.
49. Yanagi K, Tanaka T, Kato K, Sadik G, Morihara T, Kudo T, Takeda M. Involvement of puromycin-sensitive aminopeptidase in proteolysis of tau protein in cultured cells, and attenuated proteolysis of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) mutant tau. Psychogeriatrics. 2009 Dec;9(4):157-66. PubMed.
50. 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.
51. 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.
52. Mohl GA, Dixon G, Marzette E, McKetney J, Samelson AJ, PeredaSerras C, Jin J, Li A, Boggess SC, Swaney DL, Kampmann M. The disease-causing tau V337M mutation induces tau hypophosphorylation and perturbs axon morphology pathways. 2024 Jun 06 10.1101/2024.06.04.597496 (version 1) bioRxiv.
53. Goedert M, Satumtira S, Jakes R, Smith MJ, Kamibayashi C, White CL 3rd, Sontag E. Reduced binding of protein phosphatase 2A to tau protein with frontotemporal dementia and parkinsonism linked to chromosome 17 mutations. J Neurochem. 2000 Nov;75(5):2155-62. PubMed.
54. Han D, Paudel HK. FTDP-17 missense mutations site-specifically inhibit as well as promote dephosphorylation of microtubule-associated protein tau by protein phosphatases of HEK-293 cell extract. Neurochem Int. 2009 Jan;54(1):14-27. Epub 2008 Oct 15 PubMed.
55. 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.
56. 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.
57. 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.
58. 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.
59. Matsumura N, Yamazaki T, Ihara Y. Stable expression in Chinese hamster ovary cells of mutated tau genes causing frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Am J Pathol. 1999 Jun;154(6):1649-56. PubMed.
60. 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.
61. Arawaka S, Usami M, Sahara N, Schellenberg GD, Lee G, Mori H. The tau mutation (val337met) disrupts cytoskeletal networks of microtubules. Neuroreport. 1999 Apr 6;10(5):993-7. PubMed.
62. Sahara N, Tomiyama T, Mori H. Missense point mutations of tau to segregate with FTDP-17 exhibit site-specific effects on microtubule structure in COS cells: a novel action of R406W mutation. J Neurosci Res. 2000 May 1;60(3):380-7. PubMed.
63. Furukawa K, Wang Y, Yao PJ, Fu W, Mattson MP, Itoyama Y, Onodera H, D'Souza I, Poorkaj PH, Bird TD, Schellenberg GD. Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation. J Neurochem. 2003 Oct;87(2):427-36. PubMed.
64. Frappier T, Liang NS, Brown K, Leung CL, Lynch T, Liem RK, Shelanski ML. Abnormal microtubule packing in processes of SF9 cells expressing the FTDP-17 V337M tau mutation. FEBS Lett. 1999 Jul 23;455(3):262-6. PubMed.
65. Cassar M, Law AD, Chow ES, Giebultowicz JM, Kretzschmar D. Disease-Associated Mutant Tau Prevents Circadian Changes in the Cytoskeleton of Central Pacemaker Neurons. Front Neurosci. 2020;14:232. Epub 2020 Mar 27 PubMed.
66. Blard O, Feuillette S, Bou J, Chaumette B, Frébourg T, Campion D, Lecourtois M. Cytoskeleton proteins are modulators of mutant tau-induced neurodegeneration in Drosophila. Hum Mol Genet. 2007 Mar 1;16(5):555-66. Epub 2007 Feb 19 PubMed.
67. Glasauer SM, Goderie SK, Rauch JN, Guzman E, Audouard M, Bertucci T, Joy S, Rommelfanger E, Luna G, Keane-Rivera E, Lotz S, Borden S, Armando AM, Quehenberger O, Temple S, Kosik KS. Human tau mutations in cerebral organoids induce a progressive dyshomeostasis of cholesterol. Stem Cell Reports. 2022 Sep 13;17(9):2127-2140. Epub 2022 Aug 18 PubMed.
68. Sohn PD, Huang CT, Yan R, Fan L, Tracy TE, Camargo CM, Montgomery KM, Arhar T, Mok SA, Freilich R, Baik J, He M, Gong S, Roberson ED, Karch CM, Gestwicki JE, Xu K, Kosik KS, Gan L. Pathogenic Tau Impairs Axon Initial Segment Plasticity and Excitability Homeostasis. Neuron. 2019 Nov 6;104(3):458-470.e5. Epub 2019 Sep 18 PubMed.
69. Hartmann C, Anskat M, Ehrlich M, Sterneckert J, Pal A, Hermann A. MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons. Biomedicines. 2024 Mar 13;12(3) PubMed.
70. Furukawa K, D'Souza I, Crudder CH, Onodera H, Itoyama Y, Poorkaj P, Bird TD, Schellenberg GD. Pro-apoptotic effects of tau mutations in chromosome 17 frontotemporal dementia and parkinsonism. Neuroreport. 2000 Jan 17;11(1):57-60. PubMed.
71. Li Y, Munoz-Mayorga D, Nie Y, Kang N, Tao Y, Lagerwall J, Pernaci C, Curtin G, Coufal NG, Mertens J, Shi L, Chen X. Microglial lipid droplet accumulation in tauopathy brain is regulated by neuronal AMPK. Cell Metab. 2024 Jun 4;36(6):1351-1370.e8. Epub 2024 Apr 23 PubMed.
72. Liazoghli D, Perreault S, Micheva KD, Desjardins M, Leclerc N. Fragmentation of the Golgi apparatus induced by the overexpression of wild-type and mutant human tau forms in neurons. Am J Pathol. 2005 May;166(5):1499-514. PubMed.
73. Curley M, Rai M, Chuang CL, Pagala V, Stephan A, Coleman Z, Robles-Murguia M, Wang YD, Peng J, Demontis F. Transgenic sensors reveal compartment-specific effects of aggregation-prone proteins on subcellular proteostasis during aging. Cell Rep Methods. 2024 Oct 21;4(10):100875. Epub 2024 Oct 8 PubMed.
74. 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.
75. Yen S, Easson C, Nacharaju P, Hutton M, Yen SH. FTDP-17 tau mutations decrease the susceptibility of tau to calpain I digestion. FEBS Lett. 1999 Nov 12;461(1-2):91-5. PubMed.
76. Theofilas P, Wang C, Butler D, Morales DO, Petersen C, Ambrose A, Chin B, Yang T, Khan S, Ng R, Kayed R, Karch CM, Miller BL, Gestwicki JE, Gan L, Temple S, Arkin MR, Grinberg LT. iPSC-induced neurons with the V337M MAPT mutation are selectively vulnerable to caspase-mediated cleavage of tau and apoptotic cell death. Mol Cell Neurosci. 2024 Sep;130:103954. Epub 2024 Jul 20 PubMed.

Further Reading

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1. Alzheimer Disease & Frontotemporal Dementia Mutation Database