Mutations In Tau Gene Research Articles

Mechanistic Insights into Tau Protein-Mediated Regulation of Oxidative Stress.

Abnormal hyperphosphorylation and microtubule-associated protein tau aggregation development in the brain are characteristics of neurodegenerative diseases referred to as tauopathies, which include Alzheimer's disease (AD). The current review summarizes the complex relationships that exist between oxidative stress and tau illness, with particular attention to the roles played by the tau protein, reactive oxygen species and their consequences, and tau phosphorylation and oxidative stress. Two key elements of detrimental cycle that are critical in neurodegenerative tauopathies are tau hyperphosphorylation and oxidative stress. When tau and microtubules are not connected properly, microtubule instability, issues with microtubule transport, and ultimately neuronal death result. While the causes of the more prevalent sporadic late-onset variants and the connections between tau hyperphosphorylation and neurodegeneration remain largely unknown, mutations in the microtubule-associated protein tau (MAPT) gene have been identified in familial cases of early-onset tauopathies. Another detrimental feature of tauopathies is oxidative stress, but the exact role it plays in the development of the disease is unclear. The source of reactive oxygen species (ROS), which lead to oxidative stress within neural tissue, remains an unresolved topic. Although mitochondria have historically been thought to be a primary source of oxidative stress, microglial cells have recently been discovered to create reactive oxygen species in tauopathies. In conclusion, enhancing our comprehension of the impact of oxidative stress on various diseases could facilitate the identification of new disease markers and lead to the formulation of treatment strategies aimed at halting, reversing, or mitigating disease progression.

Tau protein binds to the P53 E3 ubiquitin ligase MDM2

Tau gene mutations cause a progressive dementia and neurotoxic Tau forms deposited in neurofibrillary tangles are hallmarks of neurodegenerative tauopathies. Loss of non-canonical Tau functions may contribute to disease. In fact, Tau depletion affects the cellular response to DNA damage and tauopathies exhibit the accumulation of DNA lesions. Moreover, Tau modulates P53 activity and cell fate. Considering that MDM2 is the main antagonist of P53, we investigated, using orthogonal assays, if Tau interacts with MDM2. We report the existence in cells and brain of a Tau-MDM2 complex that, in vitro, exhibits reduced P53 ubiquitination activity in a manner sensitive to a Tau mutation. The Tau-MDM2 interaction involves the microtubule-binding domain of Tau and the acidic domain of MDM2, reminiscent of the binding of Tau to negatively charged microtubules. Notably, MDM2 accumulates aberrantly in neurofibrillary tangles. Aging-associated insults may expose a novel loss-of-function of Tau in neurodegeneration and cancer.

Defective proteostasis in induced pluripotent stem cell models of frontotemporal lobar degeneration.

Impaired proteostasis is associated with normal aging and is accelerated in neurodegeneration. This impairment may lead to the accumulation of protein, which can be toxic to cells and tissue. In a subset of frontotemporal lobar degeneration with tau pathology (FTLD-tau) cases, pathogenic mutations in the microtubule-associated protein tau (MAPT) gene are sufficient to cause tau accumulation and neurodegeneration. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. Here, we show that molecular networks associated with lysosomal biogenesis and autophagic function are disrupted in brains from FTLD-tau patients carrying a MAPT p.R406W mutation. We then used human induced pluripotent stem cell (iPSC)-derived neurons and 3D cerebral organoids from patients carrying the MAPT p.R406W mutation and CRISPR/Cas9, corrected controls to evaluate proteostasis. MAPT p.R406W was sufficient to induce morphological and functional deficits in the lysosomal pathway in iPSC-neurons. These phenotypes were reversed upon correction of the mutant allele with CRISPR/Cas9. Treatment with mTOR inhibitors led to tau degradation specifically in MAPT p.R406W neurons. Together, our findings suggest that MAPT p.R406W is sufficient to cause impaired lysosomal function, which may contribute to disease pathogenesis and serve as a cellular phenotype for drug screening.

A Canadian cohort with the IVS10+14 MAPT mutation

AbstractBackgroundThe IVS10+14 microtubule‐associated protein tau gene (MAPT) mutation causes dysregulated protein splicing of MAPT, resulting in abnormal 4‐repeat isoform tau accumulation and associated with neurodegeneration. Three families expressing the IVS10+14 MAPT mutation have been reported who express the IVS10+14 MAPT mutation displaying a high degree of interfamilial heterogeneity in their clinical presentation. Herein, we describe the clinical and neuropathological presentation of a new Canadian cohort with this mutation.MethodClinical and neuropathological records, including neuropsychological and cognitive assessments, and stained neuropathological sections, were obtained for three family members with the IVS10+14 MAPT mutation. The records were reviewed and compared to previously reported families with this mutation.ResultThe Canadian cohort displayed many of the symptoms previously described in cases with the IVS10+14 MAPT mutation, including prominent motor, cognitive, behavioural, and behavioural symptoms. Additionally, consistent with the interfamilial heterogeneity described in literature, our cohort exhibited profound sensory and sleep abnormalities. Neuropathological information was available for two cases, in which one had widespread cortical and subcortical tau deposition and atrophy, while neuropathological changes in the other case was milder with the exception substantia nigral atrophy.ConclusionOur cohort demonstrate that while the IVS10+14 MAPT mutation often results in motor, cognitive and behavioural clinical features, sensory and sleep abnormalities are also manifestations of the mutation. Clinicopathological correlations were able to explain symptom presence and severity for two of the three examined cases. This underlines the need to explore alternate mechanisms and metrics of brain dysfunction in tauopathy in addition to tau burden and neuronal loss. Reference: Maxwell SP, Cash MK, Rockwood K, Fisk JD, Darvesh S. 2021. Clinical and Neuropathological Variability in the Rare IVS10+14 Tau Mutation. Neurobiology of Aging. In Press. DOI: 10.1016/j.neurobiolaging.2021.01.004.

P.014 A Novel Canadian Family with the Rare IVS10+14 Tau Mutation

Background: The IVS10+14 mutation in the microtubule-associated protein tau gene, MAPT, is a rare point mutation that dysregulates tau splicing resulting in pathological aggregation. This mutation has been identified in three families with severe neurodegenerative disease. We characterized the clinicopathological features of a fourth, Canadian family with the IVS10+14 MAPT mutation and compared them to previously reported families. Methods: Clinical and neuropathological records from three family members with the IVS10+14 MAPT mutation were reviewed. Neuropathological section from one available case were analyzed. Results: Considerable interfamilial phenotypic heterogeneity is reported in all cohorts that express the IVS10+14 MAPT mutation, with prominent motor, cognitive, behavioural, and respiratory symptoms. The Canadian cohort also expressed profound sensory and sleep abnormalities, not reported previously. In the two siblings with available neuropathological records, neuropathological changes ranged from mild to severe. Conclusions: All families expressing the IVS10+14 MAPT mutation display striking inter- and intrafamilial clinical and neuropathologic phenotypic variability. Our cohort adds sensory and sleep abnormalities as potential symptoms and illustrates a lack of clear clinicopathological correlates for these heterogenous symptoms. Reference: Maxwell et al. 2021. Clinical and Neuropathological Variability in the Rare IVS10+14 Tau Mutation. Neurobiology of Aging. In Press. DOI: 10.1016/j.neurobiolaging.2021.01.004.

Pathologic tau conformer ensembles induce dynamic, liquid-liquid phase separation events at the nuclear envelope

BackgroundThe microtubule-associated protein tau forms aggregates in different neurodegenerative diseases called tauopathies. Prior work has shown that a single P301L mutation in tau gene, MAPT, can promote alternative tau folding pathways that correlate with divergent clinical diagnoses. Using progressive chemical denaturation, some tau preparations from the brain featured complex transitions starting at low concentrations of guanidine hydrochloride (GdnHCl) denaturant, indicating an ensemble of differently folded tau species called conformers. On the other hand, brain samples with abundant, tangle-like pathology had simple GdnHCl unfolding profile resembling the profile of fibrillized recombinant tau and suggesting a unitary conformer composition. In studies here we sought to understand tau conformer progression and potential relationships with condensed liquid states, as well as associated perturbations in cell biological processes.ResultsAs starting material, we used brain samples from P301L transgenic mice containing tau conformer ensembles that unfolded at low GdnHCl concentrations and with signatures resembling brain material from P301L subjects presenting with language or memory problems. We seeded reporter cells expressing a soluble form of 4 microtubule-binding repeat tau fused to GFP or YFP reporter moieties, resulting in redistribution of dispersed fluorescence signals into focal assemblies that could fuse together and move within processes between adjacent cells. Nuclear envelope fluorescent tau signals and small fluorescent inclusions behaved as a demixed liquid phase, indicative of liquid-liquid phase separation (LLPS); these droplets exhibited spherical morphology, fusion events and could recover from photobleaching. Moreover, juxtanuclear tau assemblies were associated with disrupted nuclear transport and reduced cell viability in a stable cell line. Staining for thioflavin S (ThS) became more prevalent as tau-derived inclusions attained cross-sectional area greater than 3 μm2, indicating (i) a bipartite composition, (ii) in vivo progression of tau conformers, and (iii) that a mass threshold applying to demixed condensates may drive liquid-solid transitions.ConclusionsTau conformer ensembles characterized by denaturation at low GdnHCl concentration templated the production of condensed droplets in living cells. These species exhibit dynamic changes and develop in vivo, and the larger ThS-positive assemblies may represent a waystation to arrive at intracellular fibrillar tau inclusions seen in end-stage genetic tauopathies.

Pathogenic MAPT mutations Q336H and Q336R have isoform-dependent differences in aggregation propensity and microtubule dysfunction.

Tauopathies are a group of heterogeneous neurodegenerative disorders characterized by brain deposition of tau inclusions. These insidious disorders include Alzheimer's disease and frontotemporal dementia, the two leading causes of dementia. Mutations in the microtubule-associated protein tau (MAPT) gene lead to familial forms of frontotemporal dementia. Previously, we used cell-based assays to screen over 20 missense tau mutations and found that decreased microtubule (MT) binding affinity was the most shared property. As a break from this trend, the MAPT mutations Q336H and Q336R are thought to promote MT assembly rather than inhibit it based on in vitro studies. Q336H and Q336R MAPT mutations also cause early onset frontotemporal dementia with Pick bodies, which are mostly composed of 3R tau isoforms. To provide further insights on the pathobiology of these mutations, we assessed Q336H and Q336R tau mutants for aggregation propensity and MT binding in cell-based assays in the context of both 0N3R and 0N4R tau isoforms. Q336R tau was prone to prion-like seeded aggregation but both Q336H and Q336R tau led to increased MT binding. Additionally, we found that different tau isoforms with these mutations heterogeneously regulate different MT subpopulations of tyrosinated and acetylated MTs, markers of newly formed MTs and stable MTs. The Q336H and Q336R tau mutations may exemplify an alternative mechanism where pathogenic tau can bind MTs with higher affinity and hyperstabilize MTs, which prevent proper MT regulation and homeostasis.

Critical Molecular and Cellular Contributors to Tau Pathology.

Tauopathies represent a group of neurodegenerative diseases including Alzheimer’s disease (AD) that are characterized by the deposition of filamentous tau aggregates in the brain. The pathogenesis of tauopathies starts from the formation of toxic ‘tau seeds’ from hyperphosphorylated tau monomers. The presence of specific phosphorylation sites and heat shock protein 90 facilitates soluble tau protein aggregation. Transcellular propagation of pathogenic tau into synaptically connected neuronal cells or adjacent glial cells via receptor-mediated endocytosis facilitate disease spread through the brain. While neuroprotective effects of glial cells—including phagocytotic microglial and astroglial phenotypes—have been observed at the early stage of neurodegeneration, dysfunctional neuronal-glial cellular communication results in a series of further pathological consequences as the disease progresses, including abnormal axonal transport, synaptic degeneration, and neuronal loss, accompanied by a pro-inflammatory microenvironment. Additionally, the discovery of microtubule-associated protein tau (MAPT) gene mutations and the strongest genetic risk factor of tauopathies—an increase in the presence of the ε2 allele of apolipoprotein E (ApoE)—provide important clues to understanding tau pathology progression. In this review, we describe the crucial signaling pathways and diverse cellular contributors to the progression of tauopathies. A systematic understanding of disease pathogenesis provides novel insights into therapeutic targets within altered signaling pathways and is of great significance for discovering effective treatments for tauopathies.

Clinical and neuropathological variability in the rare IVS10 + 14 tau mutation

Mutations in the microtubule-associated protein tau gene are known to cause progressive neurodegenerative disorders with variable clinical and neuropathological phenotypes, including the intronic 10 + 14 (IVS10 + 14) splice site mutation. Three families have been reported with the IVS10 + 14 microtubule-associated protein tau mutation. Here, we describe the clinical and neuropathological data from an additional family. Neuropathological data were available for 2 of the 3 cases, III-4, and III-5. While III-5 had widespread tau deposition and atrophy, III-4 exhibited more mild neuropathological changes except for the substantia nigra. The previously reported families that express the IVS10 + 14 mutation exhibited significant interfamilial heterogeneity, with symptoms including amyotrophy, dementia, disinhibition, parkinsonism, and breathing problems. In addition to expressing many of these symptoms, members of this fourth family experienced profound sensory abnormalities and sleep disturbance. Although there were probable clinicopathological correlates for the symptoms expressed by the earlier families and III-5 from our cohort, pathology in III-4 did not appear sufficient to explain symptom severity. This indicates the need to explore alternate mechanisms of tau-induced brain dysfunction.

Factors of Cell Degeneration or Death caused by Mutant Tau Protein

Tau protein is a microtubule associated protein mainly expressed in neurons. Under pathological conditions, Tau protein is abnormally hyperphosphorylated and separated from microtubules. Abnormal Tau aggregates form nerve fiber tangles, which are insoluble aggregates in the brain. It is due to the microtubule rupture caused by Tau protein dysfunction and it is associated with neurofibrillar degeneration in Alzheimer's disease.This paper studies several reports and research on the structure and function of Tau protein, the role of Tau protein in pathological diseases and its relationship with neurodegenerative diseases. This paper concludes that Tau protein has undergone abnormal modification and aggregation in many neurodegenerative diseases, but the specific type of Tau protein that causes neurotoxicity, as well as the pathogenesis of its phosphorylation and functional injury inducing nerve apoptosis, are still not fully understood. Various abnormal modifications of Tau protein occur under pathological conditions, and fatal cascade events occur at different stages of neuron apoptosis. Therefore, the causes and effects of cytotoxicity mediated by Tau protein are very complicated. Different or even opposite conclusions are sometimes drawn in Tau protein-mediated neurodegeneration studies. This may be due to differences in Tau protein type, gene mutation and protein expression level.

Japanese Familial Cases of Frontotemporal Dementia and Parkinsonism with N279K Tau Gene Mutation.

Mutations in the tau gene linked to chromosome 17 cause frontotemporal dementia and parkinsonism (FTDP-17). This study presents 3 Japanese familial cases diagnosed with N279K tau gene mutation, including 1 autopsy-confirmed case. We compared the clinical presentations, cognitive functions, and images between the 3 familial cases diagnosed with N279K mutation. All 3 patients presented symptoms in their early 40s. One patient showed severe cognitive dysfunction and died in his sixth year after onset. The remaining 2 cases presented with parkinsonism-dominant clinical features. Among the 2 cases, 1 presented the characteristic symptoms of progressive supranuclear palsy. The pathological features of the dementia-dominant case showed frontal and temporal lobe-dominant neuronal loss and gliosis. Tau-positive neuronal and glial inclusions were found throughout. Further, tufted astrocytes and globose tangles were present whereas there were no Pick bodies and astrocytic plaques, compatible with pathology-confirmed frontotemporal lobar degeneration (FTLD) -tau subtypes. Patients with FTDP-17 can be classified into the following 2 major groups: dementia and parkinsonism-plus predominant phenotypes. Among our 3 cases, 1 showed dementia predominance whereas the other 2 showed parkinsonism predominance. Mutations in the microtubule-associated protein tau (MAPT) present with several pathological features. Clinically, our case presented a behavioral variant frontotemporal dementia (bvFTD). However, morphologically, the observed glial and neuronal pathology met the criteria for progressive supranuclear palsy (PSP). This study highlights the clinical heterogeneity within and between families with same MAPT mutation. Few pathologically confirmed PSP cases have been reported with mutations in MAPT.

The behavioural phenotype of 14-month-old female TAU58/2 transgenic mice

Frontotemporal dementia (FTD) and Alzheimer’s disease (AD) exhibit intracellular inclusions [neurofibrillary tangles (NFT’s)] of microtubule-associated protein tau that contributes to neuronal dysfunction and death. Mutations in the microtubule-associated protein tau (MAPT) gene leads to tau hyperphosphorylation and promotes NFT formation. The TAU58/2 transgenic mouse model expresses mutant human tau (P301S mutation) and exhibits behavioural abnormalities relevant to dementia in early adulthood. Here we comprehensively determined the behavioural phenotype of TAU58/2 transgenic female mice at 14 months of age using test paradigms relevant to FTD and AD.TAU58/2 females showed a significant motor deficit and lower bodyweight compared to WT littermates. Transgenic females failed to habituate to the test arena in the light-dark test. Interestingly, transgenics did not exhibit an anxiolytic-like phenotype and intermediate-term spatial learning in the cheeseboard test was intact. However, a significant learning deficit was detected in the 1st trial across test days indicating impaired long-term spatial memory. In addition, the preference for a previously rewarded location was absent in transgenic females during probe trial testing. Finally, TAU58/2 mice had a defective acoustic startle response and impaired sensorimotor gating.In conclusion TAU58/2 mice exhibit several behavioural deficits that resemble those observed in human FTD and AD. Additionally, we observed a novel startle response deficit in these mice. At 14 months of age, TAU58/2 females represent a later disease stage and are therefore a potentially useful model to test efficacy of therapeutics to reverse or ameliorate behavioural deficits in post-onset tauopapthy-related neurodegenerative disorders.

Insoluble Tau From Human FTDP-17 Cases Exhibit Unique Transmission Properties In Vivo.

One hallmark of neurodegenerative diseases is the intracellular accumulation of hyperphosphorylated tau protein, a neuronal microtubule-associated protein, into structures known as neurofibrillary tangles. Tauopathies are heterogeneous neurodegenerative diseases caused by the misfolding of the tau protein. It has been previously shown that the tau protein can spread from cell to cell in a prion-like manner. Tauopathies can be sporadic or familial, with the identification of pathogenic mutations in the microtubule-associated protein tau gene on chromosome 17 in the familial cases. Different frontotemporal dementia with parkinsonism-17 (FTDP-17) cases are associated with varying clinical presentations and types of neuropathology. We previously demonstrated that insoluble tau extracted from sporadic tauopathy human brains contain distinct tau strains, which underlie the heterogeneity of these diseases. Furthermore, these tau strains seeded tau aggregates that resemble human tau neuropathology in nontransgenic and 6hTau mice in vivo. Here, we show insoluble tau from human brains of FTDP-17 cases transmit different patterns of neuronal and glial tau pathology in vivo, similar to the sporadic tauopathies. This suggests that each of these tau mutations has unique properties that underlie the heterogeneity of FTDP-17 cases.

Picalm reduction exacerbates tau pathology in a murine tauopathy model.

Genome-wide association studies (GWAS) have identified PICALM as one of the most significant susceptibility loci for late-onset Alzheimer's disease (AD) after APOE and BIN1. PICALM is a clathrin-adaptor protein and plays critical roles in clathrin-mediated endocytosis and in autophagy. PICALM modulates brain amyloid ß (Aß) pathology and tau accumulation. We have previously reported that soluble PICALM protein level is reduced in correlation with abnormalities of autophagy markers in the affected brain areas of neurodegenerative diseases including AD, sporadic tauopathies and familial cases of frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) with mutations in the microtubule-associated protein tau (MAPT) gene. It remains unclarified whether in vivo PICALM reduction could either trigger or influence tau pathology progression in the brain. In this study, we confirmed a significant reduction of soluble PICALM protein and autophagy deficits in the post-mortem human brains of FTLD-tau-MAPT (P301L, S364S and L266V). We generated a novel transgenic mouse line named Tg30xPicalm+/-by crossing Tg30 tau transgenic mice with Picalm-haploinsufficient mice to test whether Picalm reduction may modulate tau pathology. While Picalm haploinsufficiency did not lead to any motor phenotype or detectable tau pathology in mouse brains, Tg30xPicalm+/- mice developed markedly more severe motor deficits than Tg30 by the age of 9months. Tg30xPicalm+/- had significantly higher pathological tau levels in the brain, an increased density of neurofibrillary tangles compared to Tg30 mice and increased abnormalities of autophagy markers. Our results demonstrate that Picalm haploinsufficiency in transgenic Tg30 mice significantly aggravated tau pathologies and tau-mediated neurodegeneration, supporting a role for changes in Picalm expression as a risk/sensitizing factor for development of tau pathology and as a mechanism underlying the AD risk associated to PICALM.

Pathological Progression Induced by the Frontotemporal Dementia-Associated R406W Tau Mutation in Patient-Derived iPSCs.

SummaryMutations in the microtubule-associated protein tau (MAPT) gene are known to cause familial frontotemporal dementia (FTD). The R406W tau mutation is a unique missense mutation whose patients have been reported to exhibit Alzheimer’s disease (AD)-like phenotypes rather than the more typical FTD phenotypes. In this study, we established patient-derived induced pluripotent stem cell (iPSC) models to investigate the disease pathology induced by the R406W mutation. We generated iPSCs from patients and established isogenic lines using CRISPR/Cas9. The iPSCs were induced into cerebral organoids, which were dissociated into cortical neurons with high purity. In this neuronal culture, the mutant tau protein exhibited reduced phosphorylation levels and was increasingly fragmented by calpain. Furthermore, the mutant tau protein was mislocalized and the axons of the patient-derived neurons displayed morphological and functional abnormalities, which were rescued by microtubule stabilization. The findings of our study provide mechanistic insight into tau pathology and a potential for therapeutic intervention.

Computational Investigation of RNA A-Bulges Related to the Microtubule-Associated Protein Tau Causing Frontotemporal Dementia and Parkinsonism.

Mutations in the human tau gene result in alternative splicing of the tau protein, which causes frontotemporal dementia and Parkinsonism. One disease mechanism is linked to the stability of a hairpin within the microtubule-associated protein tau (MAPT) mRNA, which contains an A-bulge. Here we employ computational methods to investigate the structural and thermodynamic properties of several A-bulge RNAs with different closing base-pairs. We find that the current amber RNA force field has a preference to overstabilize base-triple over stacked states, even though some of the A-bulges are known to prefer stacked states according to NMR studies. We further determined that if the neighboring base-pairs of A-bulges are AU, this situation can lead to base slippage. However, when the 3'-side of the A-bulge has an UA base-pair, the stacked state is stabilized by an extra interaction that is not observed in the other sequences. We suggest that these A-bulge RNA systems could be used as benchmarks to improve the current RNA force fields.

Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP

Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)–derived neurons carrying MAPT p.R406W and CRISPR/Cas9-corrected isogenic controls. We found that the expression of the MAPT p.R406W mutation was sufficient to create a significantly different transcriptomic profile compared with that of the isogeneic controls and to cause the differential expression of 328 genes. Sixty-one of these genes were also differentially expressed in the same direction between MAPT p.R406W carriers and pathology-free human control brains. We found that genes differentially expressed in the stem cell models and human brains were enriched for pathways involving gamma-aminobutyric acid (GABA) receptors and pre-synaptic function. The expression of GABA receptor genes, including GABRB2 and GABRG2, were consistently reduced in iPSC-derived neurons and brains from MAPT p.R406W carriers. Interestingly, we found that GABA receptor genes, including GABRB2 and GABRG2, are significantly lower in symptomatic mouse models of tauopathy, as well as in brains with progressive supranuclear palsy. Genome wide association analyses reveal that common variants within GABRB2 are associated with increased risk for frontotemporal dementia (P < 1 × 10−3). Thus, our systems biology approach, which leverages molecular data from stem cells, animal models, and human brain tissue can reveal novel disease mechanisms. Here, we demonstrate that MAPT p.R406W is sufficient to induce changes in GABA-mediated signaling and synaptic function, which may contribute to the pathogenesis of FTLD-tau and other primary tauopathies.

Different tau species lead to heterogeneous tau pathology propagation and misfolding

Tauopathies are a heterogeneous group of pathologies characterized by tau aggregation inside neurons. Most of them are sporadic but certain tauopathies rely on tau gene (MAPT) mutations. They particularly differ from one to another by their different neuropathological signatures e.g. lesion shapes, regions affected and molecular composition of aggregates. Six isoforms of tau exist, but they do not all co-aggregate in each tauopathy but rather have a unique signature for each one. In some tauopathies such as Alzheimer’s disease (AD), tau protein aggregation follows stereotypical anatomical stages. Recent data suggest that this progression is due to an active process of tau protein propagation from neuron-to-neuron. We wondered how tau isoforms or mutations could influence the process of tau aggregation and tau propagation. In human neuropathological material, we found that MAPT mutations induce a faster misfolding compared to tau found in sporadic AD patients. In the rat brain, we observed cell-to-cell transfer of non-pathological tau species irrespective of the tested isoform or presence of a mutation. By contrast, we found that the species of tau impact the propagation of tau pathology markers such as hyperphosphorylation and misfolding. Indeed, misfolding and hyperphosphorylated tau proteins do not spread at the same rate when tau is mutated, or the isoform composition is modified. These results clearly argue for the existence of specific folding properties of tau depending on isoforms or mutations impacting the behavior of pathological tau species.

Tau Mutations Serve as a Novel Risk Factor for Cancer.

In addition to its well-recognized role in neurodegeneration, tau participates in maintenance of genome stability and chromosome integrity. In particular, peripheral cells from patients affected by frontotemporal lobar degeneration carrying a mutation in tau gene (genetic tauopathies), as well as cells from animal models, show chromosome numerical and structural aberrations, chromatin anomalies, and a propensity toward abnormal recombination. As genome instability is tightly linked to cancer development, we hypothesized that mutated tau may be a susceptibility factor for cancer. Here we conducted a retrospective cohort study comparing cancer incidence in families affected by genetic tauopathies to control families. In addition, we carried out a bioinformatics analysis to highlight pathways associated with the tau protein interactome. We report that the risk of developing cancer is significantly higher in families affected by genetic tauopathies, and a high proportion of tau protein interactors are involved in cellular processes particularly relevant to cancer. These findings disclose a novel role of tau as a risk factor for cancer, providing new insights in the various pathologic roles of mutated tau.Significance: This study reveals a novel role for tau as a risk factor for cancer, providing new insights beyond its role in neurodegeneration. Cancer Res; 78(13); 3731-9. ©2018 AACR.

V363I and V363A mutated tau affect aggregation and neuronal dysfunction differently in C. elegans

Mutations in the microtubule-associated protein tau (MAPT) gene have been linked to a heterogeneous group of progressive neurodegenerative disorders commonly called tauopathies. From patients with frontotemporal lobar degeneration with distinct atypical clinical phenotypes, we recently identified two new mutations on the same codon, in position 363 of the MAPT gene, which resulted in the production of Val-to-Ala (tauV363A) or Val-to-Ile (tauV363I) mutated tau. These substitutions specifically affected microtubule polymerization and propensity of tau to aggregate in vitro suggesting that single amino acid modification may dictate the fate of the neuropathology. To clarify whether tauV363A and tauV363I affect protein misfolding differently in vivo driving certain phenotypes, we generated new transgenic C. elegans strains. Human 2N4R tau carrying the mutation was expressed in all the neurons of worms. The behavioral defects, misfolding and proteotoxicity caused by the tauV363A and tauV363I mutated proteins were compared to that induced by the expression of wild-type tau (tauwt). Pan-neuronal expression of human 2N4R tauWT in worms resulted in a neuromuscular defect with characteristics of a neurodegenerative phenotype. This defect was worsened by the expression of mutated proteins which drive distinct neuronal dysfunctions and synaptic impairments involving, in transgenic worms expressing tauV363A (V363A) also a pharyngeal defect never linked before to other mutations. The two mutations differently affected the tau phosphorylation and misfolding propensities: tauV363I was highly phosphorylated on epitopes corresponding to Thr231 and Ser202/Thr205, and accumulated as insoluble tau assemblies whereas tauV363A showed a greater propensity to form soluble oligomeric assemblies. These findings uphold the role of a single amino acid substitution in specifically affecting the ability of tau to form soluble and insoluble assemblies, opening up new perspectives in the pathogenic mechanism underlying tauopathies.