The HD mutation does not alter neuronal death in the striatum of Hdh(Q92) knock-in mice after mild focal ischemia.
Huntington's disease, with its dominant loss of striatal neurons, is triggered by an expanded glutamine tract in huntingtin. To investigate a proposed role for increased activation of the apoptotic cascade in mutant huntingtin's trigger mechanism, we examined huntingtin cleavage and lesion severity after mild ischemic injury in Hdh(Q92) mice. We found activation of calpain and caspase proteases and proteolysis of huntingtin in lesioned striatum. However, huntingtin fragments resembled products of calpain I, not caspase-3, cleavage and turnover was accompanied by augmented levels of full-length normal and mutant protein. By contrast, the number of apoptotic cells, total and striatal infarct size, and degree of neurologic deficit were similar in Hdh(Q92) and wild-type mice, indicating that the disease process neither strongly protected nor sensitized striatal neurons to apoptotic death. Thus, our findings do not support a role for increased apoptosis or caspase-3 cleavage in the mechanism by which mutant huntingtin triggers disease. However, they suggest that calpain activation and huntingtin regulation merit investigation as modifiers of disease progression in neurons injured by the harmful consequences of full-length mutant huntingtin.
Namura
Shobu
S
Stroke and Neurovascular Regulation, Massachusetts General Hospital, Charlestown, 02129, USA.
Hirt
Lorenz
L
Wheeler
Vanessa C
VC
McGinnis
Kim M
KM
Hilditch-Maguire
Paige
P
Moskowitz
Michael A
MA
MacDonald
Marcy E
ME
Persichetti
Francesca
F
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D003342:Corpus Striatum / Q000473:pathology*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D002154:Calpain; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases