Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract.
The neurodegenerative diseases Huntington disease, dentatorubropallidoluysian atrophy, spinocerebellar atrophy type 3, and spinal bulbar muscular atrophy are caused by expansion of a polyglutamine tract within their respective gene products. There is increasing evidence that generation of truncated proteins containing an expanded polyglutamine tract may be a key step in the pathogenesis of these disorders. We now report that, similar to huntingtin, atrophin-1, ataxin-3, and the androgen receptor are cleaved in apoptotic extracts. Furthermore, each of these proteins is cleaved by one or more purified caspases, cysteine proteases involved in apoptotic death. The CAG length does not modulate susceptibility to cleavage of any of the full-length proteins. Our results suggest that by generation of truncated polyglutamine-containing proteins, caspase cleavage may represent a common step in the pathogenesis of each of these neurodegenerative diseases.
Wellington
C L
CL
Centre for Molecular Medicine and Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
Ellerby
L M
LM
Hackam
A S
AS
Margolis
R L
RL
Trifiro
M A
MA
Singaraja
R
R
McCutcheon
K
K
Salvesen
G S
GS
Propp
S S
SS
Bromm
M
M
Rowland
K J
KJ
Zhang
T
T
Rasper
D
D
Roy
S
S
Thornberry
N
N
Pinsky
L
L
Kakizuka
A
A
Ross
C A
CA
Nicholson
D W
DW
Bredesen
D E
DE
Hayden
M R
MR
D000595:Amino Acid Sequence; D017209:Apoptosis; D000067699:Ataxin-3; D020170:Caspase 1; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D019169:Jurkat Cells; D007700:Kinetics; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma; D010455:Peptides; D011944:Receptors, Androgen / Q000737:chemistry / Q000378:metabolism; D012097:Repressor Proteins; D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity; D018911:Trinucleotide Repeats; D014407:Tumor Cells, Cultured
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D011944:Receptors, Androgen; D012097:Repressor Proteins; C095278:atrophin-1; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; D012697:Serine Endopeptidases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003546:Cysteine Endopeptidases; D020170:Caspase 1