Abstract
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.
Highlights
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 [1–3]
As for the mechanism that gives rise to this novel set of isoforms, it has been proposed that MAPT intronic sequences might have a regulatory role in the development of filamentous inclusions typical of tauopathies, since tau lesions are not reproduced in other species, not even great apes with highly similar Tau protein amino acid sequence [46]
Together with the diminished levels of W-Tau in Alzheimer’s disease patients, might suggest that intronic sequences could have a modulating effect by means of generating species-specific isoforms through determined alternative splicing mechanisms such as intron retention. Such mechanism would imply the need of finely regulated splicing mechanisms dealing with intronic sequences; an idea that can be supported by the fact that the protein saitohin is encoded within an intronic sequence of the MAPT gene [38] and that exon 4a might come evolutionary from an intron of other gene [56]
Summary
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 [1–3]. Tau is involved in a number of pathological processes, undergoing misfolding and oligomerisation into paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) [5]. These neuropathological lesions constitute a characteristic hallmark of a wide range of tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, Pick’s disease, Huntington’s disease or frontotemporal dementia with parkinsonism-17 [3,6]. MAPT, have been robustly determined to undergo alternative splicing, yielding a variety of splicing-generated isoforms [14,15] This is relevant, considering that alternative splicing is a regulated process that suffers alterations both during healthy ageing and under pathological conditions [16–18]; some of which are disease-specific and pointedly involve Tau [16,19,20]. The purpose of the present review is to highlight the great diversity of Tau isoforms mainly generated by alternative splicing and how this entails a consistent diversity functionwise; both of which get markedly and modified both with natural ageing and with age-related disorders
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