Mitochondrial dysfunction and oxidative stress are consistent features of multiple neurodegenerative diseases including Alzheimer’s disease (AD). Reductions in the α-ketoglutarate dehydrogenase complex (KGDHC), oxidative stress, diminished metabolism and neurodegeneration appear closely linked. The activity of KGDHC, a key mitochondrial enzyme complex that consists of three proteins, is markedly reduced in brains in several neurodegenerative diseases.
The overall goals of this research are to assess the cause of the reduction in KGDHC in brains from patients with neurodegenerative disease and to use cell and animal models to determine the consequences of the decline, and how the decline in activity or the consequences might be ameliorated. The reduction in KGDHC activity is not simply secondary to neurodegeneration, since the decline occurs in brain areas vulnerable to degeneration, and in regions without overt neuropathology.
Future studies will test the closely associated hypotheses that: (i) the diminished KGDHC activity in AD is due to the sensitivity of KGDHC to post-translational modifications including oxidative stress; (ii) mitochondrial function including the response to oxidant stress and release of pro-apoptotic proteins is sensitive to reductions in the KGDHC activities; (iii) neurons are particularly sensitive to diminished KGDHC; (iv) the proteins that make up the complex serve alternative functions. The experiments will determine if the reductions in KGDHC activity in brains of patients with neurodegenerative diseases are due to post-translational changes by using a combination of antibodies that detect common modifications and mass spectrometry. Experiments to determine the consequences of reduced KGDHC activities on cell function will utilize a specific inhibitor, as well as genetic manipulation of individual KGDHC subunits in multiple cell models and cell types from transgenic mice.
The research will test the role of each subunit and determine if neurons are more vulnerable than other brain cells. These experiments will test the relation of diminished KGDHC to mitochondrial membrane potentials, to the stimulation of the release of cytochrome c and to the response to oxidant challenge. Further experiments will test whether thioredoxin mediates the consequences of an inhibition of KGDHC through a linkage with cellular thiol metabolism. In summary, the sensitivity of KGDHC to multiple oxidative stressors and its importance to cellular function suggest that multiple factors converge at KGDHC to cause neurodegeneration.
Successful completion of these studies will provide new understanding of the molecular mechanisms underlying AD and other neurodegenerative diseases, and are likely to suggest new therapeutic strategies.