title: Expression of mutant huntingtin blocks exocytosis in PC12 cells by depletion of complexin II.
abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the HD gene. We reported recently that complexin II, a protein involved in neurotransmitter release, is depleted from both the brains of mice carrying the HD mutation and from the striatum of post mortem HD brains. Here we show that this loss of complexin II is recapitulated in PC12 cells expressing the HD mutation and is accompanied by a dramatic decline in Ca2+-triggered exocytosis of neurotransmitter. Overexpression of complexin II (but not complexin I) rescued exocytosis, demonstrating that the decline in neurotransmitter release is a direct consequence of complexin II depletion. Complexin II depletion in the brain may account for some of the abnormalities in neurotransmission associated with HD.
authors.affiliation: Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, United Kingdom.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Edwardson
authors.forename: Chih-Tien
authors.initials: CT
authors.lastname: Wang
authors.forename: Belvin
authors.initials: B
authors.lastname: Gong
authors.forename: Andreas
authors.initials: A
authors.lastname: Wyttenbach
authors.forename: Jihong
authors.initials: J
authors.lastname: Bai
authors.forename: Meyer B
authors.initials: MB
authors.lastname: Jackson
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Chapman
authors.forename: A Jennifer
authors.initials: AJ
authors.lastname: Morton
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C086055:HTT protein, human; C506812:Htt protein, mouse; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D009687:Nuclear Proteins; C095993:complexin II; D002118:Calcium