Several converging lines of inquiry suggest a central role for mitochondria! dysfunction in diseases of aging such as Alzheimer's disease (AD). Dysfunctional mitochondria perturb cellular activities in numerous ways including energy depletion, free radical generation and release of pro-death proteins. Thus, it is not surprising that increased attention has recently turned to the transcriptional mechanisms by which cells compensate for perturbations in mitochondrial functions. Genes involved in this adaptation include those involved in the tricarboxylic acid (TCA) cycle, the respiratory chain (e.g., cytochrome c), and mitochondrial antioxidant capacity (e.g., manganese containing mitochondrial superoxide dismutase (MnSOD). Accordingly our global hypothesis is that AD and HD result, in part, from the failure of compensatory, transcriptional mechanisms involved in adaptation to mitochondrial dysfunction. We believe this failure results from transcriptional dysregulation induced by toxic proteins (i.e., p-amyloid, mutant huntingtin) acting alone or in conjunction with the crosslinking enzyme, transglutaminase (TGase). In preliminary studies, we have shown that pharmacological suppression of TGase augments expression of a nuclear gene for a mitochondrial component, cytochrome c. In three specific aims, we will examine whether TGase can modulate the transcription of cytochrome c and MnSOD in primary cortical neurons and whether the negative modulation of these and other """"""""adaptive"""""""" responses by Tgase contributes to mitochondrial dysfunction observed in in vitro models of AD and HD. Together the studies may provide a unifying model for transcriptional dysregulation and mitochondrial dysfunction in age- associated neurodegeneration.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Winifred Masterson Burke Med Research Institute
White Plains
United States
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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
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
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

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