Grant: Operating Grant

Mutations in genes that activate a waste recycling program in cells, called autophagy, or "self-eating" are one cause of cancer and are implicated in neurodegenerative diseases including Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis (ALS). When autophagy is inhibited, excess waste consisting of damaged or old cellular components accumulates. In most cases we don't understand which specific type of cellular waste accumulates and causes disease when autophagy is inhibited. Our lab has been at the forefront of research on a new class of molecules degraded by autophagy called RNA. RNA is one of four major types of substrates in cells and is required for genes in our DNA to build cellular components and allow them to respond to their environment. Early studies had shown that autophagy degraded large amounts of RNA when cells were stressed, as in infection or disease. Now, our results demonstrate that autophagy uses an unusual mechanism to mark large clusters of RNA for degradation by autophagy. Fascinatingly, these RNA clusters are a defining feature of ALS that is believed to cause progressive motor neuron death and paralysis in this disease. Strikingly, genetic mapping studies suggest that mutations in genes that cause either inappropriate formation of RNA clusters or block their elimination by autophagy may cause ALS. We will investigate the surprising mechanisms underlying the ability of autophagy to recognize and degrade these RNA clusters in cellular and mouse models of ALS. Using mouse models, we will test whether autophagy-activating drugs used in patients to treat other diseases, could be an effective new treatment for ALS. This research therefore aims to understand a novel and fundamental process involved in ALS and help devise new means to treat this devastating disease.