Overview

Pathogenicity: Frontotemporal Dementia : Pathogenic
Clinical Phenotype: Frontotemporal Dementia
Position: (GRCh38/hg38):Chr17:46010388 C>T
Position: (GRCh37/hg19):Chr17:44087754 C>T
dbSNP ID: rs63751438
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CCG to TCG
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 10
Research Models: 8

Findings

This missense mutation has been most often associated with diseases in the frontotemporal dementia (FTD) spectrum, with clinical phenotypes varying widely, even within the same family. In the largest study to date, an international, retrospective cohort study that collected data from the Frontotemporal Dementia Prevention Initiative and the published literature, five families, including 20 carriers, were reported with diagnoses including behavioral variant FTD (bvFTD), corticobasal syndrome (CBS), progressive supranuclear palsy (PSP), and Parkinson’s disease (PD) (Moore et al., 2020, suppl tables 5-6). Phenotypes were usually aggressive with a mean age at onset of 34.3 years, mean age at death of 40.8 years, and mean disease duration of 4 years. Of note, the study included both confirmed mutation carriers, as well as family members who were assumed to be carriers based on their clinical phenotype.

P301S was first reported in a German family with early onset FTD with parkinsonism (Sperfeld et al., 1999). The reported pedigree included eight affected individuals over six generations. The proband and her mother both experienced early changes in mood, behavior, and memory, at age 25 and 30 respectively. Later in the disease course they developed movement disorders (e.g., stereotyped behavior, bradykinesia) and epilepsy. The proband's maternal grandfather was also affected, with symptom onset before age 40. He too had developed seizures, six months prior to his death at age 46. Segregation with disease could not be determined due to lack of DNA from family members other than the proband.

The same year, P301S was also reported in an Italian family with two affected individuals, a father and son dyad (Bugiani et al., 1999). Their clinical features differed, and they received distinct diagnoses: FTD for the father and corticobasal degeneration (CBD) for the son. Disease onset was in the third decade of life and progressed rapidly. Symptoms in the father started with changes in mood, memory, and concentration, followed by rigidity, apathy, visual and auditory, hallucinations and delusions. He died at age 36. Symptoms in the son started with problems moving his hand. He later developed rigidity, dystonia, supranuclear palsies, and myoclonus.

Additional families were identified in Japan (Yasuda et al., 2000, Yasuda et al., 2005), the UK (Morris et al., 2001), and Israel (Lossos et al., 2003, Werber et al., 2003, Casseron et al., 2005). Of note, the carriers described in the three Israeli studies are from the same kindred, an Algerian family of Jewish ancestry (see Z.K. Wszolek personal communication in Yasuda et al., 2005). Likewise, although not explicitly noted, the carriers described in the two Japanese studies are likely members of the same family.

Data from the five families illustrate the range of clinical phenotypes associated with P301S. As described above, carriers within the same family have received distinct diagnoses of FTD and CBD (Bugiani et al., 1999), as was also reported in the Algerian-Jewish family (Casseron et al., 2005). Moreover, while some carriers had prominent parkinsonism in the early stages of disease (Yasuda et al., 2000; Werber et al., 2003, Yasuda et al., 2005), others experienced dementia as the first, predominant symptom (Lossos et al., 2003; Yasuda et al., 2005). Again, these differences have been reported even in carriers of the same family (Yasuda 2005). Ages at onset—ranging from the 20s (e.g., Bugiani et al., 1999; Sperfeld et al., 1999) to the late 30s (e.g., Lossos et al., 2003)—and rates of disease progression are also variable, both between and within the same kindred (e.g., Lossos et al., 2003; Casseron et al., 2005). Specific phenotypic traits, such as the occurrence of seizures in patients with motor impairments, also vary (e.g., Sperfeld et al., 1999 versus Lossos et al., 2003; Yasuda et al., 2000).

P301S was absent from the gnomAD variant database (v.4.1.0, Sep 2024).

Neuropathology

Neuropathological findings vary across individuals, in line with the clinical heterogeneity described above, with pathology affecting not only frontal and temporal lobes, but subcortical regions as well. 

Neuropathological findings from the Italian mutation carrier with FTD showed frontotemporal atrophy with "knife-edge" atrophy in the fronto-orbital region. Extensive neuronal loss, vacuolation, and gliosis were documented, along with demyelination, spongiosis, and gliosis in the white matter of the prefrontal lobes. Rod-like and semi-circular inclusions were seen in cortical neurons. Pick body-like inclusions were present in neurons of the substantia nigra and thalamus among other brain regions. Extensive hyperphosphorylated tau pathology was observed in both neurons and glia (Bugiani et al., 1999).

Of note, while in this carrier, cell degeneration and brain atrophy were most prominent in frontotemporal regions, basal ganglia, and upper brainstem, in his son, diagnosed with CBD, neuropathological alterations (detected by evoked potentials and MRI) spread from parietofrontal regions on the right side to the contralateral side, followed by temporal and insular regions, basal ganglia, and upper brainstem. 

Autopsies from three Japanese carriers revealed frontal and temporal pathology, as well as pathology in the substantia nigra, globus pallidus, and subthalamic nucleus (Yasuda et al., 2005). Pathology in these subcortical regions was characterized by neuronal loss, microvacuolation, and astrocytic fibrosis, with neuropil threads, ballooned cells, and glial fibrillary tangles. The authors hypothesized that these subcortical alterations may underlie parkinsonian symptoms.

In one case, multiple markers of neuroinflammation were examined (Belluci et al., 2011). In the cortex and hippocampus, reactive microglia and infiltrating macrophages were detected, as well as the expression of pro-inflammatory molecules (IL-1b and COX-2) in both neurons and glia.

Magnetic resonance imaging revealed parieto-frontal atrophy predominantly on the right side in one case (Bugiani et al., 1999) and bilateral frontal atrophy in two other cases (Casseron et al., 2005).

Biological effects

P301S 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 P301S substitution promotes tau filament assembly and disrupts microtubule dynamics without affecting the splicing of exon 10.

Aggregation

P301S 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., Goedert et al., 1999; Spina et al., 2007; Falcon et al., 2015) and in cultured cells (e.g., Guo and Lee, 2013; Sanders et al., 2014; Holmes et al., 2014; Jackson et al., 2016; Strang et al., 2018).

In vivo experiments have been consistent with and extended these observations. For example, in transgenic mice expressing the human mutant protein, tau becomes insoluble and hyperphosphorylated over time (Yoshiyama et al., 2007).  Moreover, in vivo studies of this variant have 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 (e.g., Jun 2009 news; May 2014 news;  Oct 2014 news; Nov 2016 news; Jun 2023 news).

P301S destabilizes wildtype tau structure, lowering the threshold for the protein to enter an aggregation-prone conformation.  Experiments in vitro, in vivo, and in silico indicate that tau hexapeptides ²⁷⁵VQIINK²⁸⁰ and ³⁰⁶VQIVYK³¹¹  are normally masked in wildtype tau molecules, and their exposure fuels tau seeding and aggregation (e.g., Falcon et al., 2015; Mirbaha et al., 2018; MacDonald et al., 2019). A few amino acids in-between, including P301, seem to normally inhibit this exposure (e.g., Strang et al., 2018). The ³⁰⁶VQIVYK³¹¹ sequence in particular appears to form a metastable compact structure with the upstream ³⁰¹PGGG³⁰⁴ repeat which modulates tau’s propensity to aggregate (Chen et al., 2019).  Substituting proline 301 with a serine reduces tau thermostability (Chen et al., 2019), allowing β-sheet assembly which in turn results in tau aggregation and neurodegeneration (MacDonald et al., 2019). Indeed, using methylation to prevent cross-β sheets to form between peptides with the P301S substitution normalized protein structure (Zhou et al., 2022; Jul 2022 news).

Several studies have shown that P301S tau oligomers and small filaments are the predominant seeding species (Stancu et al., 2015; Jackson et al., 2016; Maeda et al., 2018; see Goedert and Spillantini 2019 for review).   

P301S tau forms a variety of types of filaments. For example, a cryo-electron microscopy study of filaments from the brains of two mouse models that both carry human mutant P301S tau, Tg2541 and PS19, found differences in their filament cores (Schweighauser et al., 2023). These may be due to differences in genetic backgrounds, in the tau isoforms expressed (0N4R for Tg2541 and 1N4R for PS19), and/or in the promoters driving the transgene. Also, the authors noted that the filament structures were different between brain regions in each model, and were unlike those of inclusions observed in human brains.

Proteins that influence tau oligomerization and aggregation may contribute to this heterogeneity. Indeed, a CRISPR screen in iPSC-derived neurons carrying the P301S variant identified 500 genes that modulate tau aggregation with top hits in retromer, mitochondrial, and UFMylation pathways (Jul 2023 news; Parra Bravo et al., 2024).

Although some studies have indicated cross-seeding barriers between P301S tau and other proteins (Sanders et al., 2014), certain α-synuclein strains may be able to seed P301S aggregates in mice and in cells (July 2013 news; Guo et al., 2013).

Microtubule dynamics

Several studies have found P301S alters microtubule dynamics. In vitro experiments have shown a reduced ability to promote microtubule assembly compared with wildtype tau (Bugiani et al., 1999; Spina et al., 2007; Iovino et al., 2014), with one study showing an increase in binding of soluble tubulin dimers (Elbaum-Garfinkle et al., 2014). Moreover, in cells, P301S reduced microtubule binding (Delobel et al., 2002; Xia et al., 2019). Analyses of brain extracts from PS19 mice carrying the human mutant protein also showed decreased microtubule binding (Yoshiyama et al., 2007). In addition, P301S may alter microtubule dynamics by reducing tau’s binding to protein phosphatase 2A, a  phosphatase that regulates tau’s ability to interact with and stabilize microtubules (Goedert et al., 2000).

Additional cellular processes

P301S affects multiple cellular processes, including elevating levels of the complement component C1q which may contribute to synaptic loss (Dejanovic et al., 2018; Audrain et al., 2019; Dejanovic et al., 2022), altering signaling via the p25/Cdk5 kinase pathway which may contribute to several of P301S’s deleterious effects (Seo et al., 2017), and increasing non-canonical Wnt/Ca⁺⁺ signaling (Amal et al., 2019).

Tau aggregates and oligomers may be the underlying cause of some of the disruptions. For example, one study found that P301S tau aggregates interact with and mislocalize nuclear speckle components, disrupting mRNA splicing in mouse and cell models (Apr 2021 news; Lester et al., 2021). Another study identified binding of oligomeric mutant tau to the heterogeneous nuclear ribonucleoprotein HNRNPA2B1 which interacts with N6-methyladenosine (m6A) modified RNA transcripts, reducing protein synthesis as part of the translational stress response (Sep 2021 news; Jiang et al., 2021).

Proteomic and transcriptomic analyses of the brains of mouse models expressing tau P301S suggest alterations in neuroinflammatory responses, mitochondrial energy production, cholesterol biosynthesis, and synaptic structure (e.g., Tsumagari et al., 2022; Kim et al., 2019).

In vivo localization and timing of biological effects

Mouse models expressing P301S tau have been studied in-depth providing information on the localization and timing of this mutation’s pathogenic effects. In at least two models, memory impairment and motor deficits are observed, with the former preceding the latter (e.g., Allen et al., 2002; Yoshiyama et al., 2007). Memory loss coincides with synaptic alterations, such as reduced spine density in PS19 mice (Xu et al., 2014). Moreover, in TAU58/2 mice, hyperexcitability in hippocampal neurons with tau pathology was tied to network dysfunction and learning deficits (Przybyla et al., 2020).

Tau hyperphosphorylation and seeding appear to be very early phenotypes, at least in PS19 mice, with microglial activation and synaptic damage emerging shortly after (e.g., Feb 2007 news; Yoshiyama et al., 2007; Hoffman et al., 2013; Holmes et al., 2014; López-González et al., 2015). Interestingly, overt tau pathology, involving the accumulation of 4R aggregates, develops later, eventually resulting in widespread neurofibrillary tangle-like inclusions in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. Neuronal loss and brain atrophy are initially observed in the hippocampus and then spread to other brain regions, including the neocortex and entorhinal cortex. Late-stage pathology includes neuroinflammation, altered mitochondrial function, and increased reactive oxygen species production.

Notably, several studies have identified P301S effects on glial function that may contribute importantly to in vivo phenotypes. For example, astrocytes with upregulated expression of inflammation-related genes and downregulation of bioenergetic and translation-related genes have been described (Jiwaji et al., 2022), as well as senescent astrocytes and microglia which, when removed, reduced pathology and helped preserve cognitive function (Sep 2018 news; Bussian et al., 2018). Increased oligodendrocyte turnover, which may help compensate for early myelin loss, has also been reported (Ferreira et al., 2021).

Interestingly, the AD risk variant APOE4 appears to worsen the effects of the MAPT mutation in mice. APOE4 has been reported to drive neuroinflammation (Sep 2017 news; Oct 2019 news; Apr 2021 news), increase neurodegeneration (Litvinchuk et al., 2021), and fuel cholesterol ester buildup in microglia in mice expressing MAPT P301S (Litvinchuk et al., 2024; Nov 2023 news). Also of note, in these double transgenic mice, T-cell infiltration mediated by microglia appears to help drive neurodegeneration (Mar 2023 news; Chen et al., 2023). 

P301S’s PHRED-scaled CADD score, which integrates diverse information in silico, is 26.8, above the commonly used threshold of 20 for predicting deleteriousness (CADD v1.7, Apr 2024).

Research Models

Several rodent models carrying this mutation have been generated, including the widely used PS19 and Tg2541 mouse models, both transgenic for human mutant P301S tau. In addition, these mice have been crossed with other mouse models to generate new research tools. For example, PS19 mice were crossed to APPNL-G-F knock-in mice to create the APPNL-G-F/PS19 MAPTP301S line which develops features of Alzheimer’s disease pathology (Jiang et al., 2024).

Transgenic rats expressing the mutant human gene, Tg12099, have also been generated (Ayers et al., 2024). Tau pathology in this model develops early and recapitulates several aspects seen in human FTD patients, including tau prion propagation in the corticolimbic system, formation of neurofibrillary tangles, and neurodegeneration limited to the forebrain area.

Induced pluripotent stem cells (iPSCs) carrying P301S are also being used for studying tauopathy. For example, using CRISPR/Cas9 to mutate a P301L iPSC line to P301S, heterozygote, homozygote, and P301L/P301S mutant iPSC lines were created (Karch et al., 2019). Moreover, P301S iPSCs have been differentiated into neurons which developed tauopathy phenotypes, including altered transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity (Parra Bravo et al., 2024).

Also of note, a widely used cellular biosensor relies on P301S expression to detect tau seeding capacity in animal model and postmortem brain extracts (Oct 2014 news; Holmes et al., 2014; see also May 2020 news; Kaniyappan et al., 2020).

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References

Research Models Citations

1. Tau P301S (Line PS19)
2. hTau.P301S
3. APP NL-G-F Knock-in
4. Tg12099 rat

Mutations Citations

1. MAPT P301L
2. APOE C130R (ApoE4)

News Citations

1. Cellular Biosensor Detects Tau Seeds Long Before They Sprout Pathology 9 Oct 2014
2. Widely Used Tau Seeding Assay Challenged 22 May 2020
3. Traveling Tau—A New Paradigm for Tau- and Other Proteinopathies? 15 Jun 2009
4. Like Prions, Tau Strains Are True to Form 22 May 2014
5. More Evidence That Distinct Tau Strains May Cause Different Tauopathies 23 Nov 2016
6. Tau Propagation Surprise: It Might Travel Retrogradely 30 Jun 2023
7. Too Clingy: Extra Hydrogen Bond Prompts Protein Aggregation 7 Jul 2022
8. CRISPR Screens Net Tau Partners in Human Neurons, Brain 21 Jul 2023
9. An Extra Strain on the Brain—α-Synuclein Seeds Tau Aggregation 8 Jul 2013
10. Tau, Speckle Wrecker, Disrupts the Nuclear Home 15 Apr 2021
11. Methylated RNA: A New Player in Tau Toxicity? 14 Sep 2021
12. Tau Toxicity—Tangle-free But Tied to Inflammation 5 Feb 2007
13. Are Tauopathies Caused by Neuronal and Glial Senescence? 28 Sep 2018
14. ApoE4 Makes All Things Tau Worse, From Beginning to End 20 Sep 2017
15. In Tauopathy, ApoE Destroys Neurons Via Microglia 17 Oct 2019
16. Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration 10 Apr 2021
17. Do APOE4’s Lipid Shenanigans Trigger Tauopathy? 23 Nov 2023
18. Neurodegeneration—It’s Not the Tangles, It’s the T Cells 17 Mar 2023

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1. Bugiani et al., 1999

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