期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 39, 页码 15136-15141出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0807581105
关键词
apoptosis; cell death; dopamine neurons; Ndufs4; Parkinson's disease
资金
- National Institutes of Health [ES012215]
- Korea Science and Engineering Foundation
- Howard Hughes Medical Institute
- National Institute of Child Health and Human Development [P30 HD02274]
- University of Washington National Institute of Environmental Health Sciences Center for Ecogenetics and Environmental Health [P30ES07033]
Inhibition of mitochondrial complex I is one of the leading hypotheses for dopaminergic neuron death associated with Parkinson's disease (PD). To test this hypothesis genetically, we used a mouse strain lacking functional Ndufs4, a gene encoding a subunit required for complete assembly and function of complex I. Deletion of the Ndufs4 gene abolished complex I activity in midbrain mesencephalic neurons cultured from embryonic day (E) 14 mice, but did not affect the survival of dopaminergic neurons in culture. Although dopaminergic neurons were more sensitive than other neurons in these cultures to cell death induced by rotenone, MPP+, or paraquat treatments, the absence of complex I activity did not protect the dopaminergic neurons, as would be expected if these compounds act by inhibiting complex 1. In fact, the dopaminergic neurons were more sensitive to rotenone. These data suggest that dopaminergic neuron death induced by treatment with rotenone, MPP+, or paraquat is independent of complex I inhibition.
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