Abstract
Expanded polyglutamine repeats in different proteins are the known determinants of at least nine progressive neurodegenerative disorders whose symptoms include cognitive and motor impairment that worsen as patients age. One such disorder is Huntington’s Disease (HD) that is caused by a polyglutamine expansion in the human huntingtin protein (htt). The polyglutamine expansion destabilizes htt leading to protein misfolding, which in turn triggers neurodegeneration and the disruption of energy metabolism in muscle cells. However, the molecular mechanisms that underlie htt proteotoxicity have been somewhat elusive, and the muscle phenotypes have not been well studied. To generate tools to elucidate the basis for muscle dysfunction, we engineered Caenorhabditis elegans to express a disease-associated 513 amino acid fragment of human htt in body wall muscle cells. We show that this htt fragment aggregates in C. elegans in a polyglutamine length-dependent manner and is toxic. Toxicity manifests as motor impairment and a shortened lifespan. Compared to previous models, the data suggest that the protein context in which a polyglutamine tract is embedded alters aggregation propensity and toxicity, likely by affecting interactions with the muscle cell environment.
Highlights
George Huntington first described what subsequently became known as Huntington’s Disease (HD) in 1872 in a paper titled “On Chorea” [1]
We have described a new model for the aggregation and toxicity of a disease-associated fragment of the polyQ-containing htt protein in C. elegans body wall muscle cells
This is the first time that a htt fragment of this length (Htt513) was expressed in C. elegans–all other fragments have been no longer than 171 amino acids
Summary
George Huntington first described what subsequently became known as Huntington’s Disease (HD) in 1872 in a paper titled “On Chorea” [1]. Huntington described disease symptoms as dance-like spasmodic movements that typically manifest at around 40 years of age. He noted that HD leaves the affected patient “but a quivering wreck of his former self” due to neurodegeneration and concomitant cognitive decline before causing premature death [1]. The locus was revealed via map-based cloning and the HD-associated dominant allele was shown to contain an expanded trinucleotide repeat [2]. This trinucloetide repeat encodes a destabilizing expansion of a polyglutamine (polyQ) tract in the huntingtin (htt) protein
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