(19) Modifiers of polyglutamine-containing htt protein aggregation in C. elegans

Polyglutamine (polyQ) expansions in specific proteins are the genetic provenances of nine different neurodegenerative disorders including Huntington’s Disease (HD), which causes cognitive and motor impairment. We are... [ view full abstract ]

Polyglutamine (polyQ) expansions in specific proteins are the genetic provenances of nine different neurodegenerative disorders including Huntington’s Disease (HD), which causes cognitive and motor impairment. We are interested in understanding the molecular processes of the human protein huntingtin (htt) that result in cellular toxicity. We have generated a novel model for huntingtin protein aggregation through the expression of the disease-associated polyglutamine-containing N-terminal fragment of Huntingtin (Htt513) in C. elegans body wall muscle cells. To identify modifiers of htt-associated aggregation and toxicity, we performed EMS mutagenesis on our novel model and identified three mutants having either a below average aggregate count or an above average aggregate count. We will take a gene-mapping approach to identify the mutation causing the change in overall aggregate number. Behavioral assays and lifespan analysis will reveal the influence of the identified mutation on htt-associated toxicity. The modifiers will provide an additional way to study the cellular processes underlying polyglutamine-associated toxicity.