Grant: Doctoral: Vanier Canada Graduate Scholarships

In autophagy, a variety of cytoplasmic substrates are engulfed within autophagosomes and degraded in the lysosome. Interestingly autophagy does not randomly degrade cytoplasmic content. When confronted with a particular stress environment, autophagy employs selective receptors such as p62 to link stress-specific substrates to the autophagosomes for degradation. Evidence suggests that mutations in these autophagy pathways specialized in elimination of specific substrates cause distinct neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). At the molecular level, it is not clear which specific substrate(s) cause disease when they are not eliminated by autophagy. Therefore, tailored therapeutics that affect degradation of disease-specific substrates by autophagy may be required to treat ALS. Historically, the field of autophagy has focused on proteins and organelles as the substrates for degradation, despite evidence that a major fraction of RNA is degraded by autophagy, particularly in stress. Mutated versions of several genes linked to ALS (e.g. FUS, TDP-43) cause formation of RNA-rich granules. Strikingly, we recently discovered that another ALS-linked gene - p62, recognizes these granules called stress granules (SGs), and targets them for degradation by autophagy. This suggests that inefficient clearance of SGs by autophagy may have critical roles in some forms of ALS. Mutations in ALS-linked FUS induce its arginine-methylation and accumulation in pathological SGs. Strikingly then, our preliminary evidence suggests a novel mechanism whereby the ALS-linked autophagy receptor - p62 detects arginine-methylation to eliminate stress granules. To delineate how degradation of ALS-linked stress granules contributes to pathology, we will identify RNAs degraded in this process by autophagy. With effective treatments lacking, this project therefore aims to define novel mechanisms of RNA degradation by autophagy that will provide new avenues to treat ALS.