Mechanisms of Dendrite Degeneration in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two ends of a disease spectrum. Among the many etiologies for ALS and FTD, the identification of mutations and proteinopathies in two RNA-binding proteins, TDP-43 (TARDBP or TAR DNA-binding protein 43) and its closely related RNA-/DNA-binding protein FUS (fused in sarcoma), raises the intriguing possibility that perturbations to the RNA homeostasis and metabolism in neurons may contribute to the pathogenesis of these diseases. Although the similarities between TDP-43 and FUS suggest that mutations and proteinopathy involving these two proteins may converge on the same mechanisms leading to neurodegeneration, there is emerging evidence that FUS mutations target distinct mechanisms to cause early disease onset and aggressive progression of disease. This chapter focuses on the recent advances on the molecular, cellular, and genetic approaches to uncover the mechanisms of endogenous FUS proteins in neural development and neurodegeneration. These findings provide important insights to understand how FUS mutations may perturb the maintenance of dendrites through fundamental processes in RNA splicing, RNA transport, and DNA damage response/repair. These results contribute to the understanding of phenotypic manifestations in neurodegeneration related to FUS mutations and to identify important directions for future investigations.