title: Wild-type huntingtin protects neurons from excitotoxicity.
abstract: Huntingtin is a caspase substrate, and loss of normal huntingtin function resulting from caspase-mediated proteolysis may play a role in the pathogenesis of Huntington disease. Here we tested the hypothesis that increasing huntingtin levels protect striatal neurons from NMDA receptor-mediated excitotoxicity. Cultured striatal neurons from yeast artificial chromosome (YAC)18 transgenic mice over-expressing full-length wild-type huntingtin were dramatically protected from apoptosis and caspase-3 activation compared with cultured striatal neurons from non-transgenic FVB/N littermates and YAC72 mice expressing mutant human huntingtin. NMDA receptor activation induced by intrastriatal injection of quinolinic acid initiated a form of apoptotic neurodegeneration within the striatum of mice that was associated with caspase-3 cleavage of huntingtin in neurons and astrocytes, decreased levels of full-length huntingtin, and the generation of a specific N-terminal caspase cleavage product of huntingtin. In vivo, over-expression of wild-type huntingtin in YAC18 transgenic mice conferred significant protection against NMDA receptor-mediated apoptotic neurodegeneration. These data provide in vitro and in vivo evidence that huntingtin may regulate the balance between neuronal survival and death following acute excitotoxic stress, and that the levels of huntingtin may modulate neuronal sensitivity to excitotoxic neurodegeneration. We suggest that further study of huntingtin's anti-apoptotic function will contribute to our understanding of the pathogenesis of Huntingdon's disease and provide insights into the selective vulnerability of striatal neurons to excitotoxic cell death.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, British Colombia Research Institute for Children's and Women's Health, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. bleavitt@cmmt.ubc.ca
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: van Raamsdonk
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Shehadeh
authors.forename: Herman
authors.initials: H
authors.lastname: Fernandes
authors.forename: Zoe
authors.initials: Z
authors.lastname: Murphy
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Wellington
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002110:Caffeine / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018244:Chromosomes, Artificial, Yeast; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D002110:Caffeine; D016202:N-Methylaspartate; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine