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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG014930-09
Application #
7807914
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
9
Fiscal Year
2009
Total Cost
$1,399,439
Indirect Cost
Name
Winifred Masterson Burke Med Research Institute
Department
Type
DUNS #
780676131
City
White Plains
State
NY
Country
United States
Zip Code
10605
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