Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD
Morgan R. Miller, Megan Dykstra, Sami Barmada
Morgan R. Miller, Megan Dykstra, Sami Barmada
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Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative diseases characterized by the nuclear clearance and cytoplasmic aggregation of transactive response DNA/RNA-binding protein of 43 kDa (TDP43). Alternative splicing of TARDBP, the gene encoding TDP43, leads to a surprising diversity of RNA and protein isoforms with unique functions and potential implications for disease pathogenesis. Here, we review the production, properties, and functional consequences of alternative splicing in the development of ALS and FTD, focusing primarily on TDP43 due to its integral connection with the pathogenesis of sporadic as well as familial forms of these diseases. We synthesize current evidence on the biology of alternative TARDBP splicing, highlight key questions regarding its role in TDP43 proteinopathies such as ALS and FTD, and touch on the larger phenomenon of alternative splicing and its relationship to disease.

Authors

Morgan R. Miller, Megan Dykstra, Sami Barmada

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Figure 1

TARDBP splicing gives rise to several distinct isoforms.

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TARDBP splicing gives rise to several distinct isoforms. (A) Diagram of...
(A) Diagram of the TARDBP locus, with emphasis on exon 2 and the high splicing density region (HSDR) encompassing exon 6, exon 7, and the proximal 3′ untranslated region (3′UTR). Canonical start (ATG) and stop (TAG) codons are illustrated in exons 2 and 6, respectively. Distinct splice donor (d0, d1, d2) and acceptor (a1, a2) sites are labeled in the HSDR, as well as polyadenylation (pA) signals, introns 6–8 (I6–I8), and the deletion of nt 96–106 (del96_106) in exon 2. (B) Table depicting spliced RNA isoforms and corresponding protein variants for each of the splicing events in A. Unique residues encoded by exon 7 are shown in purple (EALH), magenta (KVVL), and red (RPRL), distinguished in each case by the C-terminal 4 aa. NLS, nuclear localization signal; RRM, RNA recognition motif; NTD, N-terminal domain; LCD, low-complexity domain.