Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3‐nitropropionic acid neurotoxicity

Abstract Altered energy metabolism, including reductions in activities of the key mitochondrial enzymes α‐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.