Novel therapeutic targets for amyotrophic lateral sclerosis: ribonucleoproteins and cellular autonomy

Abstract

Introduction: Amyotrophic lateral sclerosis (ALS) is a devastating disease with a lifetime risk of approximately 1:400. It is incurable and invariably fatal. Average survival is between 3 and 5 years and patients become increasingly paralyzed, losing the ability to speak, eat, and breathe. Therapies in development either (i) target specific familial forms of ALS (comprising a minority of around 10% of cases) or ii) emanate from (over)reliance on animal models or non-human/non-neuronal cell models. There is a desperate and unmet clinical need for effective treatments. Deciphering the primacy and relative contributions of defective protein homeostasis and RNA metabolism in ALS across different model systems will facilitate the identification of putative therapeutic targets. Areas covered: This review examines the putative common primary molecular events that lead to ALS pathogenesis. We focus on deregulated RNA metabolism, protein mislocalization/pathological aggregation and the role of glia in ALS-related motor neuron degeneration. Finally, we describe promising targets for therapeutic evaluation. Expert opinion: Moving forward, an effective strategy could be achieved by a poly-therapeutic approach which targets both deregulated RNA metabolism and protein dyshomeostasis in the relevant cell types, at the appropriate phase of disease.