Splicing the narrative: alternative TARDBP splicing and its relation to neurodegeneration in ALS and FTD

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.