Presenter: Matthew William Hull
Faculty Sponsor: Joslyn Mills
School: Bridgewater State University
Research Area: Biological Organisms
Session: Poster Session 2, 11:30 AM - 12:15 PM, Auditorium, A79
ABSTRACT
Huntington's disease (HD) is an age-related neurodegenerative disease associated with the aggregation of mutant Huntingtin protein (mHTT). It is theorized that prevention or clearance of these aggregates would protect neurons from degeneration. The maintenance of proteostasis is accomplished by clearing damaged or aggregated proteins which can be carried out by two main pathways: autophagy and the ubiquitin proteasome system (UPS). Macroautophagy, further referred to as autophagy, clears proteins and other macromolecules in bulk by degrading and recycling in an autophagolysosome-dependent manner, while the UPS targets individual proteins tagged with ubiquitin to be degraded by the proteasome. A decrease in functional proteostasis could be driving the Huntingtin proteins aggregations to accumulate, progressing the disease. Using a C. elegans model of HD in a small reverse genetic screen of 100 genes on Chromosome 3, cnnm-5 was identified as a genetic modifier of mHTT accumulation. Since loss of cnnm-5 by RNAi during development protects against mHTT accumulation, cnnm-5 may be a negative regulator of protein aggregation clearance. Therefore, we hypothesized that if cnnm-5 negatively regulates proteostatic machinery, then knockdown of cnnm-5 will increase autophagy and the UPS, which leads to the observed decrease in mutant Huntingtin protein accumulation. Here we report that cnnm-5 knockdown decreases mHTT protein aggregation, upregulates both major pathways of proteostasis, increases the lifespan of the HD model of C. elegans, and protects against paralysis in the Alzheimer's disease model strain.
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