Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity
Klivenyi, P; Starkov, AA; Calingasan, NY; Gardian, G; Browne, SE; Yang, L; Bubber, P; Gibson, GE; Patel, MS; Beal, MF
HERO ID
4933535
Reference Type
Journal Article
Year
2004
Language
English
PMID
| HERO ID | 4933535 |
|---|---|
| In Press | No |
| Year | 2004 |
| Title | Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity |
| Authors | Klivenyi, P; Starkov, AA; Calingasan, NY; Gardian, G; Browne, SE; Yang, L; Bubber, P; Gibson, GE; Patel, MS; Beal, MF |
| Journal | Journal of Neurochemistry |
| Volume | 88 |
| Issue | 6 |
| Page Numbers | 1352-1360 |
| Abstract | 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. |
| Doi | 10.1046/j.1471-4159.2003.02263.x |
| Pmid | 15009635 |
| Wosid | WOS:000220050900005 |
| Is Certified Translation | No |
| Dupe Override | No |
| Is Public | Yes |
| Language Text | English |
| Keyword | Index Medicus |