Wild-type huntingtin protects from apoptosis upstream of caspase-3.
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.
Rigamonti
D
D
Institute of Pharmacological Sciences, University of Milano, 20133 Milano, Italy.
Bauer
J H
JH
De-Fraja
C
C
Conti
L
L
Sipione
S
S
Sciorati
C
C
Clementi
E
E
Hackam
A
A
Hayden
M R
MR
Li
Y
Y
Cooper
J K
JK
Ross
C A
CA
Govoni
S
S
Vincenz
C
C
Cattaneo
E
E
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
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