Regulation of alternative splicing of tau exon 10

Abstract

The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer's disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4R-tau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T (frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifi cally characterized by tau pathology) only disrupt exon 10 splicing, but do not infl uence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is suffi cient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The fi ndings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies.Keywords: alternative splicing; tau; tau exon 10; tauopathies IntroductionTau is a major neuronal microtubule-associated protein, which promotes the assembly of microtubules and stabilizes the microtubule network [1] . As a phosphoprotein, the degree of phosphorylation of tau regulates its biological functions. However, abnormally hyperphosphorylated tau easily aggregates into neurofibrillary tangles (NFTs) and deposits in the affected neurons in the brains of individuals with Alzheimer's disease (AD) [2,3] . It is believed that hyperphosphorylation of tau is responsible for its loss of biological function, gain of toxicity, and aggregation into NFTs [4][5][6] .In addition to AD, aggregation of hyperphosphorylated tau in the brain has been found in other neurodegenerative diseases, such as corticobasal degeneration (CBD), Down syndrome (DS), frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifi cally characterized by tau pathology (FTDP-17T), Niemann-Pick disease, Pick's disease, postencephalitic Parkinsonism, and progressive supranuclear palsy (PSP). These sporadic and familial neurodegenerative disorders are defi ned as "tauopathies" [7, 8] .The discovery of tau gene (MAPT) mutations causing FTDP-17Tprovides clear evidence that aberrant tau can cause neurodegeneration by itself without amyloid plaques [9] .Human tau is encoded by a single gene located on chromosome 17q21, which is composed of 16 exons. By alternative splicing of exons 2, 3, and 10, six isoforms of tau are expressed in the normal adult human brain [10] . Exon 10 encodes the second microtubule-binding repeat. Thus, [6,12] . The normal adult human brain expresses approximately equal levels of 3R-tau and 4R-tau [10, 13] . However, almo...

Altered Levels and Isoforms of Tau and Nuclear Membrane Invaginations in Huntington’s Disease

“…The high number of samples analyzed in that study allowed them to conclude that the top increment takes place in grade 2 cases regarding the mRNA and in grade 3 cases regarding the protein, resulting in higher 0N4R and lower 1N3R isoforms (St-Amour et al, 2018). All these findings regarding altered isoform ratio in HD are very relevant in view of the fact that alteration in the ratio of 4R-Tau and 3R-Tau isoforms is sufficient to cause neurodegeneration (Hutton et al, 1998;Qian and Liu, 2014), as this might contribute per se to HD neurodegeneration independently of other deleterious effects of mHtt, thus becoming a therapeutic target for HD.…”

Isoform-independent and -dependent phosphorylation of microtubule-associated protein tau in mouse brain during postnatal development

“…has been studied in relation to the balance between 3R and 4R tau in AD and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) (37). Many intron mutations in the MAPT tau gene have been found in FTDP-17, and they are reported to increase the expression ratio of 4R tau (37,38). It has been shown that the splicing in or out activity of exon 10 is regulated by the phosphorylation of serine/arginine-rich (SR) proteins in the spliceosome (39).…”

“…It has been shown that the splicing in or out activity of exon 10 is regulated by the phosphorylation of serine/arginine-rich (SR) proteins in the spliceosome (39). Although there are protein kinases that are relatively specific for SR splicing proteins, such as SR protein kinase or Cdc-like kinase (CLK/Sly) (38,39), several tau protein kinases, including GSK3␤, DYRK1, and PKA, are also reported to regulate the splicing of tau pre-mRNA by phosphorylating the particular splicing proteins (40 -44). Although their involvement in the developmental regulation of tau isoforms has not been investigated, some of these protein kinases could regulate both the splicing of tau pre-mRNA and the phosphorylation of tau protein.…”

Special Issue: Treatment of Genetic Disease

“…During AS of precursor mRNA (premRNA), different combinations of 5' and 3' splice site pairs are selected, resulting in the generation of divers mRNA and protein variants. Pre-mRNA splicing takes place within the spliceosome, a large molecular complex composed of five small nuclear ribonucleoproteins (snRNPs) U1, U2, U4, U5, U6, and approximately 50-100 non-snRNP splicing factors [18]. The spliceosome recognizes specific sequences in pre-mRNA to define intron-exon boundaries and to facilitate splicing.…”

“…Furthermore, splicing is regulated by specific nucleotide sequences found within the mRNA (cis-elements). These elements include exonic splicing enhancers, exonic splicing silencers, and intronic splicing silencers [18]. In addition to cis-elements, trans-acting factors are a group of proteins that bind to cis-elements and are composed of serine and arginine rich (SR) proteins and heterogeneous nuclear ribonucleoproteins (hnRNPs).…”