Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterized by selective motor neuron death and accumulation of insoluble proteinaceous deposits in surviving motor neurons. Mutations in Cu/Zn superoxide dismutase (SOD1) confer a toxic gain of function that causes about 20% of familial ALS cases. Mutations in SOD1 result in misfolded proteins that are toxic to cells. Misfolded proteins are a common feature of many age-related neurodegenerative diseases and are normally handled by efficient protein quality control systems including molecular chaperones and the ubiquitin-proteasome system. When these systems are impaired or overwhelmed, misfolded proteins accumulate to form aggregates, such as Lewy bodies in Parkinson's disease and neurofibrillary tangles and amyloid plaques in Alzheimer's disease. The aggresome- autophagy pathway represents another cellular defense mechanism where cytotoxic oligomers are sequestered into aggresomes, a specialized type of inclusion body. Aggresome formation facilitates misfolded protein clearance by macroautophagy (hereafter referred to as autophagy), a lysosome-dependent bulk- degradation process. Recent evidence indicates that misfolded SOD1 can form aggresome-like aggregates in the perinuclear area, but the molecular signals required for misfolded SOD1 to form these aggregates are unknown. In this project, the applicant will use a combination of biochemical, cell biological, molecular genetic, and animal model systems to investigate if misfolded SOD1 is targeted to the aggresome-autophagy pathway for degradation, and whether this mechanism is cytoprotective against misfolded SOD1-induced toxicity. Completion of this project will advance our understanding of ALS pathogenesis, and provide fundamental information for the development of novel therapeutics for ALS and related neurodegenerative disorders.
Protein misfolding is intimately linked to the pathogenesis of several age-related neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). The goal of the proposed research is to elucidate the molecular mechanisms that regulate clearance of misfolded SOD1, which have been implied in ALS pathogenesis. The results of the proposed studies will provide fundamental information needed for the development of effective therapeutics to defend against these devastating diseases.