Are proteostasis defects responsible for amyotrophic lateral sclerosis?

The pathological hallmark of Amyotrophic lateral sclerosis (ALS) is the presence of ubiquitylated protein inclusions in affected motor neurons, which is indicative of disruption in the mechanisms that maintain proteome homeostasis (proteostasis) in these cells. Moreover, many of the genes in which mutations are associated with ALS encode proteins that have important roles in the maintenance of proteostasis. It is thus hypothesised that dysfunction in the proteostasis network underlies motor neuron degeneration in ALS. Whilst proteostasis dysfunction in ALS has been a major focus of research in the past two decades, there is an urgent need to identify the precise molecular mechanisms that lead to this dysfunction. Addressing this gap in knowledge is a necessary step towards understanding what causes neurodegeneration in ALS, and to the identification of novel therapeutic targets to prevent this.