Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity.
Altered energy metabolism, including reductions in activities of the key mitochondrial enzymes alpha-ketoglutarate dehydrogenase complex (KGDHC) and pyruvate dehydrogenase complex (PDHC), are characteristic of many neurodegenerative disorders including Alzheimer's Disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Dihydrolipoamide dehydrogenase is a critical subunit of KGDHC and PDHC. We tested whether mice that are deficient in dihydrolipoamide dehydrogenase (Dld+/-) show increased vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), malonate and 3-nitropropionic acid (3-NP), which have been proposed for use in models of PD and HD. Administration of MPTP resulted in significantly greater depletion of tyrosine hydroxylase-positive neurons in the substantia nigra of Dld+/- mice than that seen in wild-type littermate controls. Striatal lesion volumes produced by malonate and 3-NP were significantly increased in Dld+/- mice. Studies of isolated brain mitochondria treated with 3-NP showed that both succinate-supported respiration and membrane potential were suppressed to a greater extent in Dld+/- mice. KGDHC activity was also found to be reduced in putamen from patients with HD. These findings provide further evidence that mitochondrial defects may contribute to the pathogenesis of neurodegenerative diseases.
Klivenyi
Peter
P
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York 10021, USA.
Starkov
Anatoly A
AA
Calingasan
Noel Y
NY
Gardian
Gabrielle
G
Browne
Susan E
SE
Yang
Lichuan
L
Bubber
Parvesh
P
Gibson
Gary E
GE
Patel
Mulchand S
MS
Beal
M Flint
MF
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D002421:Caudate Nucleus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D002452:Cell Count; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008058:Dihydrolipoamide Dehydrogenase / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006816:Huntington Disease / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D007655:Ketoglutarate Dehydrogenase Complex / Q000187:drug effects / Q000378:metabolism; D008314:Malonates; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009574:Nitro Compounds; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D011422:Propionates; D011699:Putamen / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
D008314:Malonates; D009574:Nitro Compounds; D011422:Propionates; D011768:Pyruvate Dehydrogenase Complex; C030290:malonic acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D007655:Ketoglutarate Dehydrogenase Complex; D008058:Dihydrolipoamide Dehydrogenase; C015392:3-nitropropionic acid