L-3-hydroxyacyl-CoA dehydrogenase II protects in a model of Parkinson's disease.
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.
Tieu
Kim
K
Department of Neurology, Columbia University, New York, NY 10032, USA.
Perier
Celine
C
Vila
Miquel
M
Caspersen
Casper
C
Zhang
Hui-Ping
HP
Teismann
Peter
P
Jackson-Lewis
Vernice
V
Stern
David M
DM
Yan
Shi Du
SD
Przedborski
Serge
S
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000378:metabolism; D004579:Electron Transport / Q000502:physiology; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D020267:MPTP Poisoning; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016877:Oxidants / Q000378:metabolism; D010085:Oxidative Phosphorylation; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D014475:Uncoupling Agents / Q000378:metabolism
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D007527:Isoenzymes; D018696:Neuroprotective Agents; D016877:Oxidants; D014475:Uncoupling Agents; D006861:Hydrogen Peroxide; D015094:3-Hydroxyacyl CoA Dehydrogenases; D004298:Dopamine