TY - JOUR
T1 - The HD mutation does not alter neuronal death in the striatum of HdhQ92 knock-in mice after mild focal ischemia
AU - Namura, Shobu
AU - Hirt, Lorenz
AU - Wheeler, Vanessa C.
AU - McGinnis, Kim M.
AU - Hilditch-Maguire, Paige
AU - Moskowitz, Michael A.
AU - MacDonald, Marcy E.
AU - Persichetti, Francesca
N1 - Funding Information:
The authors thank Dr. K. Wang (Pfizer, Ann Arbor MI) for generous gifts of antibody reagents and V. Vrbanac and L. Lebel for expert technical assistance. This work was supported by NINDS Grants NS16367 (M.E.M.), NS32765 (M.E.M.), and NS10828 (M.A.M.) and a grant from the Huntington’s Disease Society of America Coalition for the Cure (M.E.M.). V.C.W. was the recipient of a postdoctoral fellowship from the Hereditary Disease Foundation. L.H. was supported by fellowships from the SSMBS and SICPA Foundation. S.N. was supported by the Uehara Memorial Foundation.
PY - 2002
Y1 - 2002
N2 - 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 HdhQ92 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 HdhQ92 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.
AB - 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 HdhQ92 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 HdhQ92 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.
UR - http://www.scopus.com/inward/record.url?scp=0036451840&partnerID=8YFLogxK
U2 - 10.1006/nbdi.2002.0532
DO - 10.1006/nbdi.2002.0532
M3 - Article
SN - 0969-9961
VL - 11
SP - 147
EP - 154
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1
ER -