title: Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron.
abstract: The effect of expressing human huntingtin fragments containing polyglutamine (polyQ) tracts of varying lengths was assessed in Caenorhabditis elegans ASH sensory neurons in young and old animals. Expression of a huntingtin fragment containing a polyQ tract of 150 residues (Htn-Q150) led to progressive ASH neurodegeneration but did not cause cell death. Progressive cell death and enhanced neurodegeneration were observed in ASH neurons that coexpressed Htn-Q150 and a subthreshold dose of a toxic OSM-10::green fluorescent protein (OSM-10::GFP) fusion protein. Htn-Q150 huntingtin protein fragments formed protein aggregates in ASH neurons, and the number of ASH neurons containing aggregates increased as animals aged. ASH neuronal cell death required ced-3 caspase function, indicating that the observed cell death is apoptotic. Of interest, ced-3 played a critical role in Htn-Q150-mediated neurodegeneration but not in OSM10::GFP-mediated ASH neurodegeneration. ced-3 function was important but not essential for the formation of protein aggregates. Finally, behavioral assays indicated that ASH neurons, coexpressing Htn-Q150 and OSM10::GFP, were functionally impaired at 3 days before the detection of neurodegeneration, cell death, and protein aggregates.
authors.affiliation: Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Faber
authors.forename: J R
authors.initials: JR
authors.lastname: Alter
authors.forename: M E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: A C
authors.initials: AC
authors.lastname: Hart
mesh_terms: D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D001522:Behavior, Animal; D017173:Caenorhabditis elegans / Q000235:genetics; D029742:Caenorhabditis elegans Proteins; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015801:Helminth Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009475:Neurons, Afferent / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D014110:Touch
chemical_list: D029742:Caenorhabditis elegans Proteins; C086055:HTT protein, human; D015801:Helminth Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; C097188:polyglutamine; D020169:Caspases; D003546:Cysteine Endopeptidases; C089223:ced-3 protein, C elegans