Identifying Liver Proteins that Decrease Mutant SOD1 Misfolding and Decrease SOD1

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Mutant SOD1 has been implicated in familial forms of amyotrophic lateral sclerosis, a disease marked by the progressive loss of motor neurons in the spinal cord, with concomitant weakness, atrophy of skeletal muscles, loss of motor function, paralysis, and eventual death from respiratory failure in 3-5 years post diagnosis. SOD1 is a ubiquitous protein responsible for scavenging oxygen free radicals; thus, how mutations in such a widely expressed protein result in tissue specific toxicity remains a mystery. One hypothesis asserts that the toxicity of SOD1 results from its misfolding and aggregation. Support for this hypothesis stems from the observation that mutant SOD1 forms aggregates in brain and spinal cord, but not in the liver or other non central nervous system tissues. We are now using a variety of biochemical techniques to characterize proteins from liver that apparently have a protective effect on SOD1 misfolding. Future experiments include the purification, identification, and characterization of the liver factor, with the ultimate goal of a novel patient therapy. PUBLIC HEALTH RELEVANCE: The goal of this study is to identify the protein or proteins in the liver that lead to normal handling of SOD1 protein despite the mutations. Spinal cord neurons degenerate and have evidence of misfolded, aggregated SOD1. The ultimate goal of this study is to modify the pathway identified or add back the proteins identified to enhance the ability of spinal cord to clear/handle the misfolded protein and thus decrease the neurotoxicity. This could lead to a novel treatment for ALS and, perhaps, other neurodegenerative diseases.