title: Decreasing Levels of the cdk5 Activators, p25 and p35, Reduces Excitotoxicity in Striatal Neurons.
abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG trinucleotide repeat sequence in the huntingtin gene. The resulting poly-glutamine expansion in the huntingtin protein imparts a novel toxic gain of function causing selective loss of medium spiny neurons (MSNs) in the striatum. Although the exact mechanism of cell death is unclear, recent evidence suggests involvement of NMDA-receptor mediated excitotoxicity and aberrant cyclin dependent kinase 5 (cdk5) activity in striatal cells undergoing neurodegeneration. In this study we directly tested the effect of reduced levels of p25 and p35, two proteins required for cdk5 activation, on striatal neurodegeneration using mice with targeted deletion of p35. Quinolinic acid (QA) injected into the striatum of mice causes NMDA-receptor mediated cell death, and these QA-induced striatal lesions were examined in p35 hemizygous null (p35+/-) and wildtype (WT) mice. Striatal QA lesion volumes were 30% smaller in p35+/- mice than in WT mice. Furthermore, primary neuronal cultures of MSNs from P0 p35+/- pups displayed 33% less apoptotic neurons following NMDA treatment than those from WT pups. Examination of YAC128 mouse model of HD showed elevated p25 levels in striatum following intrastriatal QA injection. Our findings provide direct evidence for p25 and p35 involvement in excitotoxic neurodegeneration of MSNs and suggest a role for the cdk5 pathway in HD striatal neurodegeneration.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Kevin H J
authors.initials: KH
authors.lastname: Park
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ge
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Psychiatry, Brain Research Centre, University of British Columbia, Vancouver, BC, Canada ; Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada ; Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D010770:Phosphotransferases / Q000378:metabolism*
chemical_list: C492236:Cdk5r1 protein, mouse; D009498:Neurotoxins; D016202:N-Methylaspartate; D010770:Phosphotransferases
keywords: Huntington’s disease; NMDA; YAC128; cdk5; excitotoxic; medium spiny neuron; neurodegeneration; p25; quinolinic acid; striatum