The alpha-ketoglutarate dehydrogenase complex in neurodegeneration

Altered energy metabolism is characteristic of many neurodegenerative disor ders. Reductions in the key mitochondrial enzyme complex, the alpha-ketoglu tarate dehydrogenase complex (KGDHC), occur in a number of neurodegenerativ e disorders including Alzheimer's Disease (AD). The reductions in KGDHC act ivity may be responsible for the decreases in brain metabolism, which occur in these disorders. KGDHC can be inactivated by several mechanisms, includ ing the actions of free radicals (Reactive Oxygen Species, ROS). Other stud ies have associated specific forms of one of the genes encoding KGDHC (name ly the DLST gene) with AD, Parkinson's disease, as well as other neurodegen erative diseases. Reductions in KGDHC activity can be plausibly linked to s everal aspects of brain dysfunction and neuropathology in a number of neuro degenerative diseases. Further studies are needed to assess mechanisms unde rlying the sensitivity of KGDHC to oxidative stress and the relation of KGD HC deficiency to selective vulnerability in neurodegenerative diseases. (C) 2000 Elsevier Science Ltd. All rights reserved.