CHARACTERIZATION OF HUMAN HUNTINGTIN 513 AGGREGATION AND PROTEOTOXICITY IN C. ELEGANS BODY WALL MUSCLE CELLS
AuthorSands, Lester Paul III
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Sands, Lester SandsHuntingtonProteinSenior2017.pdf
Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by the insidious onset of choreiform movements (rapid, jerky involuntary movements), cognitive decline, and early death. Huntington’s Disease is caused by a polyglutamine (polyQ) expansion in the human Huntingtin protein (Htt) that induces Htt protein misfolding and cytotoxic aggregation later in life. The expanded polyQ tracts embedded within Htt target the protein for pro‐apoptotic caspase cleavage, and the formation of nuclear inclusions by Htt fragments is reported to contribute to the neurodegeneration and dysregulated muscle tissue metabolism canonical of HD. Of note, the activities of polyQ‐expanded Htt in HD neuropathology have been well studied, whereas the molecular pathways by which aggregated Htt confers diseaseassociated muscle tissue phenotypes have been incompletely described. To investigate tissue phenotypes mediated by Htt aggregation, it is purposeful to utilize simple model organisms that accurately recapitulate Htt molecular pathology in target tissues. To this end, the Kikis laboratory expressed disease‐associated, polyQ‐containing Htt fragments within body wall muscle cells of Caenorhabditis elegans and assessed muscle tissue phenotype throughout aging. I report that the Htt fragments aggregate and confer cytotoxicity in a polyQ lengthdependent manner in C. elegans body wall muscle cells, with tissue toxicity manifesting as decreased motility and curtailed lifespan. Apart from introducing a novel, biologically relevant model of Htt fragment toxicity in muscle cells, the data presented herein corroborates the notion that Htt‐associated toxicity, and more generally the nature of polyQ protein‐protein interactions within tissue microenvironments, is based on inherent protein characteristics and not simply an artifact of protein overexpression.