The activity of alpha-ketoglutarate dehydrogenase (KGDHC), a key enzyme of the tricarboxylic acid cycle is reduced in brains of individuals with neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Wernicke Korsakoff syndrome. The reduction in KGDHC activity is not just secondary to neurodegeneration, since the decline occurs not only in brain areas selective vulnerable to degeneration but also in areas without overt neuropathology. The surprising frequency of the decline in KGDHC activity suggests that this is an important response to neuronal injury and may be critical step in the cascade of events that leads to eventual death. A reasonable explanation for the decline in activity is that KGDHC is particularly sensitive to a variety of cellular insults and that in select regions the reduction in activity diminishes the cell's ability to respond to further insults resulting in neurodegeneration. For example, KGDHC in pulmonary cells is particularly sensitive to free radicals and the resulting deficit in KGDHC interferes with subsequent cellular responses. Understanding both the mechanism by which KGDHC activity is decreased in neuronal injury and the consequences of impaired KGDHC activity on cellular signal transduction systems may be helpful for the development of therapeutic strategies to reverse neurodegeneration resulting from a number of noxious events including oxidative stress. The experiments will use a neuron-like cell line (PC12 cells) and primary cultures of neurons, microglia and astrocytes to test a hypothesis with two interactive components (1) KGDHC activity is especially sensitive to factors known to lead to cell death (e.g., excess reactive oxygen species or elevated calcium) or to abnormal proteins associated with neurodegeneration (e.g., mutant presenilins or amyloid-beta-peptide). (2) As a corollary, cellular functions are sensitive to even mild reductions in KGDHC activities. The role of KGDHC in cellular processes will be assess as a function of cellular membrane potentials, calcium homeostasis and level of reactive oxygen species. The underlying basis for the enhanced sensitivity of KGDHC will be determined by treating the cells and then examining the molecular changes in KGDHC. Together, these studies will provide a mechanistic test of whether the sensitivity of KGDHC to external factors is a critical step in a cascade of events that leads to neuronal death in several neurodegenerative disorders including Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute on Aging Initial Review Group (NIA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Winifred Masterson Burke Med Research Institute
White Plains
United States
Zip Code
Tapias, Victor; Jainuddin, Shari; Ahuja, Manuj et al. (2018) Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Hum Mol Genet 27:2874-2892
Garg, Ankur; Hannan, Abdul; Wang, Qian et al. (2018) FGF-induced Pea3 transcription factors program the genetic landscape for cell fate determination. PLoS Genet 14:e1007660
Franich, Nicholas R; Basso, Manuela; André, Emily A et al. (2018) Striatal Mutant Huntingtin Protein Levels Decline with Age in Homozygous Huntington's Disease Knock-In Mouse Models. J Huntingtons Dis 7:137-150
Karuppagounder, Saravanan S; Zhai, Yujia; Chen, Yingxin et al. (2018) The interferon response as a common final pathway for many preconditioning stimuli: unexpected crosstalk between hypoxic adaptation and antiviral defense. Cond Med 1:143-150
Ratan, Rajiv R (2017) Building on NeuroNEXT: Next generation clinics to cure chronic neurological disability. Ann Neurol 82:859-862
Starkov, Anatoly A; Chinopoulos, Christos; Starkova, Natalia N et al. (2017) Divalent cation chelators citrate and EDTA unmask an intrinsic uncoupling pathway in isolated mitochondria. J Bioenerg Biomembr 49:3-11
Chen, Huanlian; Xu, Hui; Potash, Samuel et al. (2017) Mild metabolic perturbations alter succinylation of mitochondrial proteins. J Neurosci Res 95:2244-2252
Shurubor, Yevgeniya I; D'Aurelio, Marilena; Clark-Matott, Joanne et al. (2017) Determination of Coenzyme A and Acetyl-Coenzyme A in Biological Samples Using HPLC with UV Detection. Molecules 22:
Zille, Marietta; Karuppagounder, Saravanan S; Chen, Yingxin et al. (2017) Neuronal Death After Hemorrhagic Stroke In Vitro and In Vivo Shares Features of Ferroptosis and Necroptosis. Stroke 48:1033-1043
Gibson, Gary E; Thakkar, Ankita (2017) Interactions of Mitochondria/Metabolism and Calcium Regulation in Alzheimer's Disease: A Calcinist Point of View. Neurochem Res 42:1636-1648

Showing the most recent 10 out of 195 publications