(17) Intrinsic characteristics of polyglutamine-containing htt protein determines proteotoxicity 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. The... [ 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. The polyglutamine expansion destabilizes the huntingtin protein (htt) causing misfolding and subsequent neurodegeneration. The molecular mechanisms that underlie htt proteotoxicity are not well understood. To generate the tools needed to address this, we have generated a novel model for huntingtin protein aggregation by expressing the disease-associated, polyglutamine-containing, N-terminal fragment of huntingtin (Htt513) in C. elegans body wall muscle cells. We have characterized the effects of polyglutamine expansion-mediated toxicity in C. elegans through expression of the Htt513 proteins fragments in body wall muscle cells or in neurons. We demonstrate that the Htt513 protein aggregates in a polyQ-length dependent manner and that there is a correlation between aggregation and toxicity, which manifests as motor dysfunction and a significantly shortened lifespan. Taken together with previous findings, the data indicate that the protein context in which a polyglutamine tract is embedded likely influences the interactions between the polyglutamine-containing proteins and the cellular environment, which in turn seem to modulate aggregation propensity and toxicity.