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 dozens of families and hundreds of individuals worldwide. The largest study to date, an international, retrospective cohort study, collected data from 59 families and 234 individuals carrying the P301L variant from the Frontotemporal Dementia Prevention Initiative and the published literature (Moore et al., 2020). Of note, this study included both confirmed mutation carriers, as well as family members who were assumed to be carriers based on their clinical phenotype.

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). In the largest study, 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, epigenetic, 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). A complicating factor is that the genetic and phenotypic factors underlying classifications of at least some P301L-associated conditions are not always consistent and still under investigation. Indeed, as reported in a preprint, a study of monozygotic twins and a comparison of genetic (mostly P301L-associated) versus sporadic cases of semantic dementia (svFTD/svPPA), concluded that, although there are svFTD/svPPA-like syndromes with an apparent genetic etiology, "true" svFTD/svPPA is likely sporadic (Henderson et al., 2024).    

Also of note, many studies have reported patterns of autosomal dominant inheritance in FTD 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; Jiang et al., 2021; 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 | Biological Effects | Aggregation | Microtubule dynamics | Additional subcellular effects | Localization and timing of biological effects

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 (summarized in Karch et al., 2019, Table 1). In the temporal lobes, gray matter loss appears to occur predominantly in the lateral temporal lobes, while the medial temporal lobe is relatively spared (Whitwell et al., 2009). 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 contributed to the understanding of P301L-associated pathology. In a study using machine learning techniques to characterize patterns of regional atrophy in MAPT-associated FTD, nine of 10 P301L carriers that could be subtyped were assigned to the frontotemporal subtype, associated with executive dysfunction and characterized by early-stage atrophy in the orbitofrontal cortex, ventromedial prefrontal cortex, lateral temporal lobe, anterior insula cortex, and anterior cingulate (Young et al., 2021). Consistent with this analysis, as summarized in a review, most reported carriers with bvFTD had bilateral atrophy of frontal and temporal regions (Villa et al., 2024).

However, multiple examples of heterogeneity have been reported in brain imaging studies, with some carriers having atrophy predominantly on the left side, one having generalized cortical atrophy, another hippocampal involvement, and another parietal atrophy (Villa et al., 2024). 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 is in the highly conserved PGGG repeat of the second repeat domain within tau’s microtubule-binding domain. It affects only 4-repeat (4R) tau isoforms because it is in exon 10 which is spliced out of 3-repeat (3R) isoforms. The P301L substitution promotes tau filament assembly and disrupts microtubule dynamics without affecting the splicing of exon 10.

Aggregation
Isolates from human brains show selective aggregation of mutant 4R tau over 3R tau protein, with aggregates including both mutant and native tau molecules (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 and Gamblin, 2012; Strang et al., 2018; Xia et al., 2019). Compared to wildtype oligomers, P301L oligomers appear to be relatively large, with increased helical content and heightened resistance to proteolytic cleavage (Bhopatkar et al., 2024). They can incorporate wildtype monomers to generate cross-seeded species.

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). Moreover, P301L tau's interactions with negatively charged membrane lipids can result in the formation of thick patches and fibrillary structures (Ury-Thiery et al., 2024). 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 (Sep 2024 news; 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. Of note, the number of N-terminal repeats in tau harboring P301L (2N4R, 1N4R, or 0N4R) appears to have little impact on the mutation's effects on aggregation, with the mutation enhancing aggregation similarly in all isoforms (Mutreja et al., 2019). The only exception was the rate of polymerization, which was moderately reduced by the mutation in the 2N4R isoform, but not in the 1N4R or 0N4R isoforms.

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; Combs and Gamblin 2012), with one study suggesting the magnitude of the effect is dependent on the number of N-terminal exons in tau isoforms 2N4R, 1N4R, and 0N4R (Mutreja et al., 2019). The mutation may also 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). 

In addition to affecting the direct binding of tau to tubulin/microtubules, P301L may alter microtubule dynamics in other ways. For example, one report showed P301L reduces tau’s binding to protein phosphatase 2A, an enzyme that regulates tau’s ability to interact with and stabilize microtubules (Goedert et al., 2000). Also, 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), stress granule formation (Bhagat et al., 2023; Sep 2023 news), 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. It is also possible that downregulation of multiple long noncoding RNAs (lncRNAs) may underlie several of P301L's deleterious effects (Bhagat et al., 2023; Sep 2023 news). For example, iPSC-derived neurons and postmortem brain samples from P301L carriers expressed reduced levels of SNHG8—a lncRNA that binds both tau and TIA1, a protein that forms stress granules. 

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). 

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 the 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. Could “Big Tau” Protect Brain Regions from Tangles? 12 Sep 2024
10. Survey of Tau Partners Highlights Synaptic, Mitochondrial Roles 27 Jan 2022
11. Invasion of the Microtubules: Mutant Tau Deforms Neuronal Nuclei 19 Jan 2019
12. Protecting Proteasomes from Toxic Tau Keeps Mice Sharp 24 Dec 2015
13. Missing ‘Lnc’? Long Noncoding RNAs Bind Tau, Tame Stress Granules 22 Sep 2023
14. Led Astray: Pathology Tied to “Grid Cell” Malfunction in Tauopathy Model 27 Jan 2017
15. Stem Cell Model Nails Link Between Tauopathy and GABAergic Dysfunction 21 Dec 2018
16. With Tau in Synapses, NO Neurovascular Coupling 21 Aug 2020
17. Adenosine Receptors Rev Up Immune Response, Memory Loss, in Tau Model 9 Oct 2019
18. Network Analysis Points to Distinct Effects of Amyloid, Tau 25 Jan 2015

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1. Methods 6 Feb 2018

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