Tau and neurodegenerative disorders

Motoi, Yumiko; Sahara, Naruhiko; Kambe, Taiki

doi:10.1515/bmc.2010.017

Cited by 5 publications

(8 citation statements)

References 146 publications

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“…Tau truncation can take place at N-terminal or C-terminal regions [6,22,41,44,46,48,52,63,64]. Recently, a truncated toxic Tau fragment raised upon asparagine endopeptidase (AEP) cleavage, has been reported in mice model of AD and elderly and Alzheimer's disease human brains [63].…”

Section: Introductionmentioning

confidence: 99%

A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer’s disease

et al. 2021

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Tauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer’s patients’ brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer’s disease and other tauopathies.

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Section: Introductionmentioning

confidence: 99%

A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer’s disease

et al. 2021

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“…In fact, as mentioned, exon 3 requires the inclusion of exon 2 to be able to be included itself, a process which mechanisms have not yet been fully explained [ 35 ]. Alternative splicing of exons 2 and 3 result in Tau isoforms with 0, 1, or 2 inserts in the N-terminal domain, known as 0N, 1N, and 2N isoforms, respectively [ 2 , 48 ].…”

Section: Tau Alternative Splicing: Diversity Of Formsmentioning

confidence: 99%

“…Tau protein belongs to the microtubule-associated proteins (MAP) family and is encoded by the single-copy microtubule-associated protein Tau gene ( MAPT ), which is located on chromosome 17q21 in humans and consists of 16 exons [ 1 , 2 , 3 ]. Tau participates on different physiological functions, including microtubule assembly and stabilisation [ 3 ], neurite outgrowth and axonal transport [ 3 ], and regulates neuronal activity, neurogenesis and long-term depression (LTD) [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

What’s in a Gene? The Outstanding Diversity of MAPT

Ruiz-Gabarre

Carnero-Espejo

Ávila

et al. 2022

Cells

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Tau protein is a microtubule-associated protein encoded by the MAPT gene that carries out a myriad of physiological functions and has been linked to certain pathologies collectively termed tauopathies, including Alzheimer’s disease, frontotemporal dementia, Huntington’s disease, progressive supranuclear palsy, etc. Alternative splicing is a physiological process by which cells generate several transcripts from one single gene and may in turn give rise to different proteins from the same gene. MAPT transcripts have been proven to be subjected to alternative splicing, generating six main isoforms in the central nervous system. Research throughout the years has demonstrated that the splicing landscape of the MAPT gene is far more complex than that, including at least exon skipping events, the use of 3′ and 5′ alternative splice sites and, as has been recently discovered, also intron retention. In addition, MAPT alternative splicing has been showed to be regulated spatially and developmentally, further evidencing the complexity of the gene’s splicing regulation. It is unclear what would drive the need for the existence of so many isoforms encoded by the same gene, but a wide range of functions have been ascribed to these Tau isoforms, both in physiology and pathology. In this review we offer a comprehensive up-to-date exploration of the mechanisms leading to the outstanding diversity of isoforms expressed from the MAPT gene and the functions in which such isoforms are involved, including their potential role in the onset and development of tauopathies such as Alzheimer’s disease.

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“…the tau aggregation and may be present at the interface between Asn368 and Ser320, such as hydrogen bonding between the amido group of Asn368 and hydroxyl-group of Ser320. However, we are unable to exclude the possibility that the S320A by guest on November 3, 2020 http://www.jbc.a number of pathogenic missense mutations on MAPT have been reported, and their effects on tau function were also assessed experimentally(38,42). Among them, single amino-acid deletion mutants ΔK280 and ΔN296 have been reported to lose their ability for MT assembly, and ΔK280 also showed increased filament formation and the local structural changes observed in the second repeat domain of this mutant(39,40,50).…”

mentioning

confidence: 91%

“…Asn368 is responsible for AD-tau seeding 10 ability of tau, as seen for single-residue deletion mutants ΔK280 and ΔN296(38)(39)(40).…”

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confidence: 92%

Asparagine residue 368 is involved in Alzheimer's disease tau strain–specific aggregation

Shimonaka

Matsumoto

Elahi

et al. 2020

Journal of Biological Chemistry

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In tauopathies, tau forms pathogenic fibrils with distinct conformations (termed ‘tau strains’) and acts as an aggregation “seed” templating the conversion of normal tau into isomorphic fibrils. Previous research showed that the aggregation core of tau fibril covers the carboxy-terminal region (243–406) and differs among the diseases. However, the mechanisms by which distinct fibrous structures are formed and inherited via templated aggregation are still unknown. Here, we sought to identify the key sequences of seed-dependent aggregation. To identify sequences for which deletion reduces tau aggregation, SH-SY5Y cells expressing a series of 10 partial deletion (Del 1–10, covering 244–400 aa) mutants of tau-CTF24 (243–441 aa) were treated with tau seeds prepared from a different tauopathy patient’s brain [Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD)] or recombinant tau and then, seed-dependent tau aggregation was assessed biochemically. We found that the Del 8 mutant lacking 353–368 aa showed significantly decreased aggregation in both cellular and in vitro models. Furthermore, to identify the minimum sequence responsible for tau aggregation, we systematically repeated cellular tau aggregation assays for the delineation of shorter deletion sites and revealed that Asn368 mutation suppressed tau aggregation triggered by an AD-tau seed, but not using other tauopathies seeds. Our study suggested that 353–368 aa is a novel aggregation-responsible sequence other than PHF6 and PHF6*, and within this sequence, the Asn368 residue plays a role in strain-specific tau aggregation in different tauopathies.

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Tau and neurodegenerative disorders

Cited by 5 publications

References 146 publications

A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer’s disease

A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer’s disease

What’s in a Gene? The Outstanding Diversity of MAPT

Asparagine residue 368 is involved in Alzheimer's disease tau strain–specific aggregation

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