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Review
. 2022 Mar 1;11(5):840.
doi: 10.3390/cells11050840.

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

Daniel Ruiz-Gabarre  1   2   3 , Almudena Carnero-Espejo  1   3 , Jesús Ávila  2   4 , Vega García-Escudero  1   2   3
Affiliations
Review

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

Daniel Ruiz-Gabarre et al. Cells. .

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.

Keywords: Alzheimer’s disease; MAPT; Tau protein; alternative splicing; intron retention.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation and summary of the mechanisms of alternative splicing. Pre-mRNA from a hypothetical gene is displayed with 4 exons (E1–E4, green) and 3 introns (I1–I3, light orange). Below, schematic representations of the different mechanisms of alternative splicing is evidenced as different potential alternative splicing decisions marked with purple branches as opposed to black branches for constitutive splicing decisions. RNA and protein fragments marked in violet and purple (mutually exclusive exons and alternative 3′ and 5′ splicing sites) show the differences with respect to constitutive splicing. “AAAA” (alternative polyadenylation) represents a polyadenylated sequence. RNA and protein fragments marked in light orange (intron retention) point out intronic regions that are maintained instead of spliced out, while the black dashed line represents the constitutive splicing decision that would happen if intron retention did not take place.
Figure 2
Figure 2
Alternative splicing of the MAPT gene. (A) Schematic representation of the splicing process. The MAPT gene is shown with its 16 exons highlighted in different colours. Exon 0 and part of exon 1 comprise the 3′ untranslated region while the end of exon 13 and exon 14 make up the 5′ untranslated region and are all marked in grey. Constitutive exons (exons 1, 4, 5, 7, 9, 11, 12 and part of exon 13) are displayed in green. Exons 2, 3, 4a, 6, 8 and 10 are subjected to alternative splicing and have their own colours (purple, pink, violet, blue, orange and yellow, respectively). The dark-grey stripped fragment in the intron between exons 9 and 10 (S.) represents the nested gene encoding the protein saitohin. The red stripped region in the intronic area between exons 12 and 13 (I12) represents the part of intron 12 that is retained in W-Tau isoforms of Tau. The colour patterns are maintained in the RNA splicing schematic representation, stripped boxes symbolising splicing decisions that would be responsible for truncated isoforms of Tau. Finally, the longest isoform of Tau described is depicted below, including all the constitutive exons and exons 2, 3, 4a, 6 and 10 from those subjected to alternative splicing. (B) Representation of the main type of isoforms of Tau that can arise from the alternative splicing of the exons depicted above. The six main isoforms found in the Central Nervous System are displayed on the first box, including 4R and 3R isoforms with 0, 1 or 2 N-terminal inserts. For isoforms including exons 4a (Big Tau) or 6 or retaining intron 12 (W-Tau), only the 4R2N isoforms are depicted, but note that all combinations are potentially possible.
Figure 3
Figure 3
Translation of truncated Tau isoforms lacking the C-terminus. (A) Nucleotide and amino acid sequence of exon 6, flanked by exons 5 and 7. The alternative 3′ splice sites of exon 6 that generate a shift of the reading frame are indicated with black arrows within the exon sequence. The sequence resulting from such frameshifts in the proximal and distal sites are specified below. (B) Nucleotide sequence of the end of exon 12 and the beginning of intron 12 and the amino acid sequence that would be translated into upon intron 12 retention, giving rise to truncated W-Tau isoforms.
Figure 4
Figure 4
Functional regions of Tau protein. (A) Schematic representation of the equivalence between Tau amino acids translated from each exon and regional functions of Tau protein. (B) Differences on the length of different functional regions due to the inclusion or exclusion of exons 2, 3 and 10, indicated by vertical stripes. Tau 441 (4R2N) and Tau 352 (3R0N) are shown to highlight the differences. (C) Differences on the length of different functional regions of Tau due to the expansion of the protein with respect to Tau 441 (4R2N). Inclusion of exon 4a (pink, squared area) implies the extension of the N-terminal region, while inclusion of exon 6 (blue, horizontally stripped area) extends the molecule including a proline-rich exon that would extend the proline-rich region. (D) Differences on the length of Tau functional regions in isoforms lacking the C-terminal region. 6p and 6d isoforms lack the proline-rich region, the microtubule-binding region and the C-terminal end altogether, while W-Tau isoforms only lose the C-terminal end. Blue, diagonally stripped regions on isoforms 6p and 6d represent the translation of their respective specific sequences, which can have their own functions. Red stripped regions on the W-Tau isoform represent the unique 18 amino acid sequence characteristic of these isoforms, which may also have specific properties.
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References

    1. Buée L., Bussière T., Buée-Scherrer V., Delacourte A., Hof P.R. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res. Rev. 2000;33:95–130. doi: 10.1016/S0165-0173(00)00019-9. - DOI - PubMed
    1. Motoi Y., Sahara N., Kambe T., Hattori N. Tau and neurodegenerative disorders. Biomol. Concepts. 2010;1:131–145. doi: 10.1515/bmc.2010.017. - DOI - PubMed
    1. Wang Y., Mandelkow E. Tau in physiology and pathology. Nat. Rev. Neurosci. 2016;17:22–35. doi: 10.1038/nrn.2015.1. - DOI - PubMed
    1. Guo T., Noble W., Hanger D.P. Roles of tau protein in health and disease. Acta Neuropathol. 2017;133:665–704. doi: 10.1007/s00401-017-1707-9. - DOI - PMC - PubMed
    1. Kovacech B., Novak M. Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer’s disease. Curr. Alzheimer Res. 2010;7:708–716. doi: 10.2174/156720510793611556. - DOI - PubMed