title: Wild-type huntingtin protects from apoptosis upstream of caspase-3.
abstract: Expansion of a polyglutamine sequence in the N terminus of huntingtin is the gain-of-function event that causes Huntington's disease. This mutation affects primarily the medium-size spiny neurons of the striatum. Huntingtin is expressed in many neuronal and non-neuronal cell types, implying a more general function for the wild-type protein. Here we report that wild-type huntingtin acts by protecting CNS cells from a variety of apoptotic stimuli, including serum withdrawal, death receptors, and pro-apoptotic Bcl-2 homologs. This protection may take place at the level of caspase-9 activation. The full-length protein also modulates the toxicity of the poly-Q expansion. Cells expressing full-length mutant protein are susceptible to fewer death stimuli than cells expressing truncated mutant huntingtin.
authors.affiliation: Institute of Pharmacological Sciences, University of Milano, 20133 Milano, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Rigamonti
authors.forename: J H
authors.initials: JH
authors.lastname: Bauer
authors.forename: C
authors.initials: C
authors.lastname: De-Fraja
authors.forename: L
authors.initials: L
authors.lastname: Conti
authors.forename: S
authors.initials: S
authors.lastname: Sipione
authors.forename: C
authors.initials: C
authors.lastname: Sciorati
authors.forename: E
authors.initials: E
authors.lastname: Clementi
authors.forename: A
authors.initials: A
authors.lastname: Hackam
authors.forename: M R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: J K
authors.initials: JK
authors.lastname: Cooper
authors.forename: C A
authors.initials: CA
authors.lastname: Ross
authors.forename: S
authors.initials: S
authors.lastname: Govoni
authors.forename: C
authors.initials: C
authors.lastname: Vincenz
authors.forename: E
authors.initials: E
authors.lastname: Cattaneo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology; D003342:Corpus Striatum / Q000166:cytology; D015971:Gene Expression Regulation, Enzymologic; D020287:In Situ Nick-End Labeling; D016296:Mutagenesis / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology*; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014162:Transfection; D051020:bcl-X Protein
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases