Proteomic Impact of Peripheral Expression of Mutant Huntingtin in C. elegans

Huntington's Disease (HD), a neurodegenerative disorder, is caused by the expansion of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin protein (HTT), resulting in HTT aggregation. While associated with neurodegeneration, HTT is expressed ubiquitously throughout the body, leading to potential peripheral consequences of aggregation. However, the impact on peripheral tissues remains poorly understood in comparison to the central nervous system. Here, a Caenorhabditis elegans (C. elegans) HD model that expresses an N-terminal HTT fragment (nonpathogenic 15Q or pathogenic 128Q) in body-wall muscle cells was used to evaluate proteome remodeling. Four conditions (15Q and 128Q on days 2 and 7 of adult worms, denoted as 15D2, 15D7, 128D2, and 128D7) were evaluated. In comparison to 15D2, 128D2 worms displayed decreased expression of ribosomal proteins and cytoskeletal components such as actin, profilin, calponin, and myosin, as well as overexpression of galectin, a stress- and inflammation-associated protein. By day 7, the 15D7 animals exhibited developmental signatures related to ribosome biogenesis, signal transduction, and vesicle trafficking, whereas abundance levels of proteins associated with stress response pathways such as proteostasis, protein folding, and cytoskeletal remodeling were observed to be increased in the 128D7 worms. These findings demonstrate the stage-dependent, nonlinear nature of HD-associated proteome disruption associated with peripheral expression of HD.