title: Novel polyglutamine model uncouples proteotoxicity from aging.
abstract: Polyglutamine expansions in certain proteins are the genetic determinants for nine distinct progressive neurodegenerative disorders and resultant age-related dementia. In these cases, neurodegeneration is due to the aggregation propensity and resultant toxic properties of the polyglutamine-containing proteins. We are interested in elucidating the underlying mechanisms of toxicity of the protein ataxin-3, in which a polyglutamine expansion is the genetic determinant for Machado-Joseph Disease (MJD), also referred to as spinocerebellar ataxia 3 (SCA3). To this end, we have developed a novel model for ataxin-3 protein aggregation, by expressing a disease-related polyglutamine-containing fragment of ataxin-3 in the genetically tractable body wall muscle cells of the model system C. elegans. Here, we demonstrate that this ataxin-3 fragment aggregates in a polyQ length-dependent manner in C. elegans muscle cells and that this aggregation is associated with cellular dysfunction. However, surprisingly, this aggregation and resultant toxicity was not influenced by aging. This is in contrast to polyglutamine peptides alone whose aggregation/toxicity is highly dependent on age. Thus, the data presented here not only describe a new polyglutamine model, but also suggest that protein context likely influences the cellular interactions of the polyglutamine-containing protein and thereby modulates its toxic properties.
authors.affiliation: Biology Department, The University of the South, Sewanee, Tennessee, United States of America.
authors.forename: Nakeirah T M
authors.initials: NT
authors.lastname: Christie
authors.affiliation: Biology Department, The University of the South, Sewanee, Tennessee, United States of America.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Lee
authors.affiliation: Biology Department, The University of the South, Sewanee, Tennessee, United States of America.
authors.forename: Hannah G
authors.initials: HG
authors.lastname: Fay
authors.affiliation: Biology Department, The University of the South, Sewanee, Tennessee, United States of America.
authors.forename: Amelia A
authors.initials: AA
authors.lastname: Gray
authors.affiliation: Biology Department, The University of the South, Sewanee, Tennessee, United States of America.
authors.forename: Elise A
authors.initials: EA
authors.lastname: Kikis
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000067699:Ataxin-3; D017173:Caenorhabditis elegans / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D018869:Heat-Shock Response; D006801:Humans; D008969:Molecular Sequence Data; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009687:Nuclear Proteins / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D010455:Peptides / Q000378:metabolism*; D066263:Protein Aggregation, Pathological; D017510:Protein Folding; D012097:Repressor Proteins / Q000737:chemistry*
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D012097:Repressor Proteins; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3