Tau exon 10 alternative splicing and tauopathies

TLDR

Tau protein abnormalities, particularly altered 3R/4R isoform ratios from exon 10 alternative splicing, drive neurofibrillary degeneration in tauopathies. The review aims to elucidate tau exon 10 splicing regulation, its dysregulation in tauopathies, and to identify therapeutic targets. The authors examine tau gene structure, transcript variants, protein isoforms, and the regulatory mechanisms controlling exon 10 splicing. Mutations that disrupt tau exon 10 splicing, without altering the protein sequence, are sufficient to cause frontotemporal dementia, demonstrating that dysregulation of exon 10 splicing and the 3R/4R balance can drive neurodegeneration.

Abstract

Abnormalities of microtubule-associated protein tau play a central role in neurofibrillary degeneration in several neurodegenerative disorders that collectively called tauopathies. Six isoforms of tau are expressed in adult human brain, which result from alternative splicing of pre-mRNA generated from a single tau gene. Alternative splicing of tau exon 10 results in tau isoforms containing either three or four microtubule-binding repeats (3R-tau and 4R-tau, respectively). Approximately equal levels of 3R-tau and 4R-tau are expressed in normal adult human brain, but the 3R-tau/4R-tau ratio is altered in the brains in several tauopathies. Discovery of silence mutations and intronic mutations of tau gene in some individuals with frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), which only disrupt tau exon 10 splicing but do not alter tau's primary sequence, demonstrates that dysregulation of tau exon 10 alternative splicing and consequently of 3R-tau/4R-tau balance is sufficient to cause neurodegeneration and dementia. Here, we review the gene structure, transcripts and protein isoforms of tau, followed by the regulation of exon 10 splicing that determines the expression of 3R-tau or 4R-tau. Finally, dysregulation of exon 10 splicing of tau in several tauopathies is discussed. Understanding the molecular mechanisms by which tau exon 10 splicing is regulated and how it is disrupted in tauopathies will provide new insight into the mechanisms of these tauopathies and help identify new therapeutic targets to treat these disorders.