title: p35 hemizygosity activates Akt but does not improve motor function in the YAC128 mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a hereditary neurodegenerative disorder resulting from N-terminal polyglutamine expansion in the huntingtin protein. A relatively selective and early loss of medium spiny neurons in the striatum is a hallmark of HD neuropathology. Although the exact mechanism of mutant huntingtin-mediated neurodegeneration is unclear, recent evidence suggests that NMDA-receptor-mediated excitotoxicity is involved. Our previously published findings show that decreasing levels of the cdk5 activators, p35 and p25, reduces NMDA receptor-mediated excitotoxicity in striatal neurons in vivo. In this study we directly examined the effect of reducing levels of p35 and p25 in the context of mutant huntingtin toxicity, using the B6 YAC128 mouse model of HD. Our findings demonstrate that deletion of a single allele of p35 in the B6 YAC128 mice results in an upregulation of Akt activity, and increases phosphorylation of mutant huntingtin at Ser421. Longitudinal behavioral analysis showed that this 50% reduction in p35 and p25 levels did not improve accelerating Rotarod performance in these YAC128 mice. However, a complete deletion of p35 normalized the accelerating Rotarod performance relative to their non-transgenic littermates at four months of age.
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada. Electronic address: park1kh@cmich.edu.
authors.forename: Kevin H J
authors.initials: KHJ
authors.lastname: Park
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Sonia
authors.initials: S
authors.lastname: Franciosi
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Kristina
authors.initials: K
authors.lastname: Parrant
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Ge
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada; Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada. Electronic address: bleavitt@cmmt.ubc.ca.
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D002154:Calpain / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics*; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D010455:Peptides / Q000235:genetics; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D045442:Rotarod Performance Test
chemical_list: C492236:Cdk5r1 protein, mouse; D000071058:Huntingtin Protein; D010455:Peptides; C097188:polyglutamine; D010770:Phosphotransferases; D051057:Proto-Oncogene Proteins c-akt; D018844:Cyclin-Dependent Kinases; D002154:Calpain
keywords: Huntington’s disease; P25; P35; YAC128 mouse model; mutant huntingtin; transgenic mice