Oxidative stress and mitochondrial dysfunction in cellular models of neurodegeneration

Neurodegenerative diseases such as Parkinson’s disease and Amyotrophic Lateral Sclerosis have an unusually high proteostatic burden due to protein misfolding, leading to the disruption of mitochondrial homeostasis and the cellular proteostatic machinery. In this thesis, I investigate how oxidative stress and mitochondrial dysfunction intersect to drive the toxicity and aggregation of the disease-associated proteins CHCHD2/CHCHD10, TDP-43 and Alpha-Synuclein. I show that CHCHD2 and CHCHD10 form high-molecular weight aggregates under oxidative stress, with CHCHD2 showing increased mitochondrial localization. Next, TDP-43 toxicity was exacerbated in respiring cells but was mitigated by growth under caloric restriction conditions. The co-expression of mistranslating tRNAs further exacerbated TDP-43 toxicity in aging cells synergistically. These results uncover conserved stress pathways that regulate protein toxicity and aggregation relevant to neurodegenerative disease pathogenesis.