Proteomic Profiling Reveals Systemic Effects of Peripheral mHtt Expression in Huntington’s Disease

Huntington's Disease (HD) is a neurodegenerative condition triggered by the elongation of a polyglutamine (polyQ) segment located at the N-terminus of the huntingtin protein (HTT). This elongation leads to the aggregation of HTT, which is ubiquitously expressed, suggesting that its aggregation may have effects beyond neurodegeneration to include peripheral tissues. However, the consequences of HTT aggregation in peripheral regions are not as thoroughly understood as those in the central nervous system. In this study, we utilized a Caenorhabditis elegans (C. elegans) model of HD, which expresses either a non-pathogenic (15Q) or a pathogenic (128Q) N-terminal fragment of HTT in body-wall muscle cells, to investigate changes in the proteome. We examined four conditions—15Q and 128Q at two different time points (days 2 and 7 of adulthood, labeled as 15D2, 15D7, 128D2, and 128D7). Compared to the 15D2 worms, those with the 128Q expansion at day 2 exhibited reduced levels of ribosomal proteins and cytoskeletal elements such as actin, profilin, calponin, and myosin, alongside an increased expression of galectin, a protein linked to stress and inflammation. By day 7, the 15D7 worms displayed developmental markers indicative of ribosome biogenesis, signal transduction, and vesicle trafficking. Meanwhile, increased levels of proteins related to stress response pathways—including proteostasis, protein folding, and cytoskeletal remodeling—were observed in the 128D7 worms. These findings elucidate the complex, stage-specific disruptions within the HD proteome tied to the expression of the disease in peripheral tissues.