Abstract
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) impairs mitochondrial respiration and damages dopaminergic neurons as seen in Parkinson's disease (PD). Here, we report that L-3-hydroxyacyl-CoA dehydrogenase type II/amyloid binding alcohol dehydrogenase (HADH II/ABAD), a mitochondrial oxidoreductase enzyme involved in neuronal survival, is downregulated in PD patients and in MPTP-intoxicated mice. We also show that transgenic mice with increased expression of human HADH II/ABAD are significantly more resistant to MPTP than their wild-type littermates. This effect appears to be mediated by overexpression of HADH II/ABAD mitigating MPTP-induced impairment of oxidative phosphorylation and ATP production. This study demonstrates that HADH II/ABAD modulates MPTP neurotoxicity and suggests that HADH II/ABAD mimetics may provide protective benefit in the treatment of PD.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3-Hydroxyacyl CoA Dehydrogenases / genetics
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3-Hydroxyacyl CoA Dehydrogenases / metabolism*
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Animals
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Antiparkinson Agents / therapeutic use*
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Disease Models, Animal
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Dopamine / metabolism
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Dopamine Agents / metabolism
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Electron Transport / physiology
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Female
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Humans
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Hydrogen Peroxide / metabolism
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Isoenzymes / genetics
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Isoenzymes / metabolism
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MPTP Poisoning
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Male
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Mesencephalon / cytology
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Mesencephalon / metabolism
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Mesencephalon / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitochondria / metabolism*
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Neuroprotective Agents / therapeutic use*
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Oxidants / metabolism
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Oxidative Phosphorylation
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Parkinsonian Disorders / chemically induced
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Parkinsonian Disorders / drug therapy*
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Parkinsonian Disorders / metabolism*
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Uncoupling Agents / metabolism
Substances
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Antiparkinson Agents
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Dopamine Agents
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Isoenzymes
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Neuroprotective Agents
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Oxidants
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Uncoupling Agents
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Hydrogen Peroxide
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3-Hydroxyacyl CoA Dehydrogenases
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Dopamine