Tau mis-splicing in the pathogenesis of neurodegenerative disorders

Abstract

Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis-splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the cis-element, methylation of the MAPT gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders. [BMB Reports 2016; 49(8): 405-413]

Gene mutations in a Han Chinese Alzheimer's disease cohort

“…We found two rare MAPT (p.Q230R in exon 6 and p.V48L in exon 3) variations, which might be benign polymorphisms. As described previously, MAPT gene consists of 16 exons and expresses six isoforms in the human brain by alternative mRNA splicing of exons 2, 3, 4A, 6, 8, and 10 (Goedert & Spillantini, 2011;Park, Ahn, & Gallo, 2016), of which exons 6 and 8 are not expressed in any major brain isoforms (Rademakers, Cruts, & Broeckhoven, 2004). Interestingly, the exon 3 is spliced only when exon 2 is present Sergeant, Delacourte, & Buee, 2005); however, the exons 3 and 2 isoforms are expressed minimally .…”

“…As described previously, MAPT gene consists of 16 exons and expresses six isoforms in the human brain by alternative mRNA splicing of exons 2, 3, 4A, 6, 8, and 10 (Goedert & Spillantini, 2011;Park, Ahn, & Gallo, 2016), of which exons 6 and 8 are not expressed in any major brain isoforms (Rademakers, Cruts, & Broeckhoven, 2004). As described previously, MAPT gene consists of 16 exons and expresses six isoforms in the human brain by alternative mRNA splicing of exons 2, 3, 4A, 6, 8, and 10 (Goedert & Spillantini, 2011;Park, Ahn, & Gallo, 2016), of which exons 6 and 8 are not expressed in any major brain isoforms (Rademakers, Cruts, & Broeckhoven, 2004).…”

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

“…As previously commented, in some Tauopathies including PSP, CB, Pick's disease (PiD) and FTLD with Tau+ inclusions (FTLD-Tau), alteration of alternative splicing of exon 10 produces an imbalance in 4R-Tau and 3R-Tau isoforms (Park et al, 2016). Regarding HD, we demonstrated that patients (and mouse models of the disease, like the R6/1 and HD94 mice) show an increase in the ratio 4R-Tau/3R-Tau mRNA isoforms in cortex and striatum, accompanied by an increase of the levels of 4R-Tau protein.…”

Investigation of the intercellular transmission of α-synuclein, amyloid-β and TDP-43

“…Further complicating matters, AD and FTLD contain mixtures of 3R and 4R, the ratio of which (i.e. 3R tau:4R tau) is thought to play a role in their respective pathologies 150,151 . In each of these disorders, misfolded, aggregated and post-translationally modified tau are deposited into protease-resistant intracellular NFTs.…”