Characterization of human Huntingtin 513 aggregation and proteotoxicity in C. elegans
Abstract
Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by the insidious onset of choreiform movements, cognitive decline, and early death. Huntington’s Disease is caused by a... [ view full abstract ]
Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by the insidious onset of choreiform movements, cognitive decline, and early death. Huntington’s Disease is caused by a polyglutamine (polyQ) expansion that induces misfolding and aggregation of human Huntingtin protein (Htt) later in life. The expanded polyQ tracts embedded within Htt target it for pro-apoptotic caspase cleavage, which may be the prerequisite for the formation of nuclear inclusions. Such inclusions are reported to contribute to neurodegeneration and dysregulated muscle tissue metabolism. To investigate tissue phenotypes mediated by Htt aggregation, we engineered a simple model organism that accurately recapitulates Htt molecular pathology in target tissues. Specifically, we expressed disease-associated, polyQ-containing Htt fragments within body wall muscle cells of Caenorhabditis elegans and assessed protein aggregation, lifespan, and muscle tissue phenotype throughout ageing. I report that the Htt fragments aggregate and confer cytotoxicity in a polyQ length-dependent 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 in my honors thesis corroborate 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.
Authors
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Paul Sands
(Sewanee - The University of the South)
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Elise Kikis
(Sewanee: The University of the South, Department of Biology, Program in Biochemistry)
Topic Area
Biochemistry
Session
OS-E » Oral Session E (Biology) (09:00 - Friday, 28th April, Woods Laboratories (Blackman Auditorium))
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