Huntingtin is degraded to small fragments by calpain after ischemic injury.
The gene defect in Huntington's disease (HD) causes a polyglutamine expansion in the N-terminal region of huntingtin (N-htt). In vitro studies suggest that mutant N-htt fragments can aggregate and cause cell death in HD. The physiological and pathological conditions that affect htt proteolysis in the brain are unclear. We examined htt expression by Western blot in the rat brain after transient ischemic injury, which causes striatal neurodegeneration similar to that seen in HD and activates proteases including calcium-dependent calpains. Focal brain ischemia reduced levels of full-length htt in the infarcted cortex and striatum and increased expression of a 55-kDa N-htt fragment that was also produced by treating control brain extracts with calpain. N-htt fragments between 65 and 80 kDa also rose after injury, but these fragments were not as long-lived as the 55-kDa N-htt fragment. The results suggest that after ischemic injury full-length htt is degraded in degenerating neurons and an N-htt fragment accumulates.
Kim
Manho
M
Department of Neurology, Clinical Research Institute, Seoul National University Hospital, Seoul, South Korea.
Roh
Jae-Kyu
JK
Yoon
Byung Woo
BW
Kang
Lami
L
Kim
Yun J
YJ
Aronin
Neil
N
DiFiglia
Marian
M
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002154:Calpain / Q000378:metabolism*; D016923:Cell Death; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D000071058:Huntingtin Protein; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley
C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D002154:Calpain