Tau splicing and the intricacies of dementia

Abstract

Tau is a microtubule-associated protein that fulfills several functions critical for neuronal formation and health. Tau discharges its functions by producing multiple isoforms via regulated alternative splicing. These isoforms modulate tau function in normal brain by altering the domains of the protein, thereby influencing its localization, conformation, and post-translational modifications and hence its availability and affinity for microtubules and other ligands. Disturbances in tau expression result in disruption of the neuronal cytoskeleton and formation of tau structures (neurofibrillary tangles) found in brains of dementia sufferers. More specifically, aberrations in tau splicing regulation directly cause several neurodegenerative diseases, which lead to dementia. In this review, I present our cumulative knowledge of tau splicing regulation in connection with neurodegeneration and also briefly go over the still-extensive list of questions that are connected to tau (dys)function.

Fig. 1

Tau mRNA species and the functions of the ensuing domains. (A) Schematic representation of exons and splicing pathways in the tau gene. Black = constitutive; white = regulated (A = adult-specific, PNS = specific to the peripheral nervous system, C = complex, ? = unknown); horizontal stripes = transcribed, untranslated regions; vertical stripes = alternative/additional reading frames. A_n indicate polyadenylation sites. The numbers underneath the exons indicate the possible number of outcomes from each alternatively spliced region within the tau transcript. (B) Diagram of the longest tau isoform. Above the diagram the general nature of the domain is noted. Below the diagram is a list of domain functions and of diseases in which the splicing of that particular region is or may be altered. (C) Schematic depictions of tau isoforms abundant in the central nervous system. On the left is the length of each isoform in amino acids, on the right its relative abundance in brain. Below the diagrams is a scale bar (aa=amino acids) and the drawing conventions for exons 2, 3 and 10.

Fig. 2

Cis elements and trans factors involved in the splicing regulation of tau exon 10. (A) Mutations of exon 10 found in pedigrees of neurodegenerative diseases (the exception is Delta11, designated by an asterisk, which was defined by the behavior of deletion constructs). The sequence of exon 10 (uppercse) and its proximal downstream intron (lowercase) is shown. Point mutations are indicated, as well as their resulting missense mutations, if any. Deletions are underlined. The only mutation not shown is P301L/S, which does not affect splicing. The boxed regions define enhancers (gray) or silencers (white). Also shown is the complementarity of the 5′ splice site with the U1 snRNA. Lines are Crick/Watson pairs, dots are G-T pairs. The effect of each mutation on exon 10 splicing is listed on the right. (B) Cumulative model of splicing interactions for tau exon 10. Cis elements that act as silencers (gray) and enhancers (striped) are indicated (not to scale). For the trans factors, binding to an enhancer implies that the factor activates splicing, whereas binding to a silencer implies that the factor inhibits it. For the factors, circles depict RNA recognition (RRM) domains, rectangles protein interaction (RS) domains. Factors whose identity and mechanisms of action have been confirmed are shades of gray, whereas factors whose details of action are speculative are white. Deletions and FTDP mutations are indicated as well as a double mutation (M280) which weakens the purine-rich enhancer.