Tau exon 10 alternative splicing and tauopathies

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.

Figure 1

The gene, mRNA and protein isoforms of tau. In tau genomic structure (top panel), the black boxes represent constitutive exons, and the gray and empty boxes represent alternative spliced exons. The middle panel demonstrates mRNAs of tau in adult human brain. A total six mRNAs are generated by alternative splicing of exons 2, 3 and 10, which is indicated by alternative lines linking these exons. The lower panel shows six isoforms of tau in adult human brain. Gray boxes represent the N-terminal inserts (coded by exons 2 and 3) or MT-binding repeats (coded by exons 9, 10, 11 and 12). The second MT-binding repeat coded by exon 10 is highlighted by dark gray box. The commonly used terms for each tau isoform are listed at the right side of the isoforms.

Figure 2

Structure of exon 10 and intron 10 of tau gene. Exon 10 is shown in capital letters and part of the franking intron 9 and intron 10 are shown in lowercase. The first half of exon 10 has three exonic splicing enhancers (SC35-like, PPE and ACE). A central exon splicing silencer (ESS) separates the 5' ESE elements from a less characterized ESE at the 3'-end of exon 10. Intron 10 elements include a bipartile intronic splicing silencer (ISS) and an adjacent intronic splicing modulator (ISM). In the interface between exon 10 and intron 10, there is a stem-loop structure. Mutations that cause an increase (red), decrease (dark green) or not yet known change (black) in the ratio of 4R/3R-tau are indicated. Triangles indicate deletion mutations.