How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other?

Abstract

This review examines the recent research developments aimed at defining the role of RNA-binding proteins (TDP-43 and FUS) in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TAR DNA-binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) are RNA-binding proteins that form aggregates in ALS and FTLD, and when mutated can drive the pathogenesis of these disorders. However, fundamental questions remain as to the relationship between TDP-43 and FUS aggregation and disease, their normal and pathologic function, and where they converge on the same cellular pathways. Autopsy series point to distinct molecular actions as TDP-43 and FUS neuronal inclusions do not overlap, with FUS inclusions being present in only a small subgroup of patients. By contrast, modeling experiments in lower organisms support a genetic interaction between TDP-43 and FUS, although it is likely indirect. Regardless, the recent finding that additional RNA-binding proteins may also cause ALS, and the observation that TDP-43 aggregation remains a core feature in all of the recently identified genetic forms of ALS (C9ORF72, VCP, UBQLN2, and PFN1), underscores the central role of TDP-43 and RNA metabolism in ALS and FTLD. Recent discoveries point to an unprecedented convergence of molecular pathways in ALS and FTLD involving RNA metabolism. Defining the exact points of convergence will likely be key to advancing therapeutics development in the coming years.