UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration

Neurodegenerative diseases are a leading cause of disability and early death. A common feature of these conditions is disruption of protein homeostasis. Ubiquitin-like modifier activating enzyme 1 (UBA1), the E1 ubiquitin-activating enzyme, sits at the apex of the ubiquitin cascade and represents an important regulator of cellular protein homeostasis. Critical contributions of UBA1-dependent pathways to the regulation of homeostasis and degeneration in the nervous system are emerging, including specific disruption of UBA1 in spinal muscular atrophy (SMA) and Huntington's disease (HD). In this review we discuss recent findings that put UBA1 at the centre of cellular homeostasis and neurodegeneration, highlighting the potential for UBA1 to act as a promising therapeutic target for a range of neurodegenerative diseases. Disruption of protein homeostasis is an important feature of many neurodegenerative diseases. The E1 ubiquitin-activating enzyme UBA1 sits at the apex of ubiquitin pathways, playing a critical role in regulating protein homeostasis. UBA1 regulates a diverse range of cellular processes in the nervous system.UBA1 contributes to the pathogenesis of several neurodegenerative diseases, including SMA and HD. In SMA, decreased UBA1 expression leads to perturbations in ubiquitin homeostasis, aberrant accumulation of downstream target proteins, and neuromuscular degeneration. In HD, UBA1 expression decreases over time, leading to selective accumulation of toxic forms of huntingtin protein in the brain.UBA1 represents a novel and promising therapeutic target for the treatment of neurodegenerative diseases.