Neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are very common and devastating disorders of aging. The primary causes for sporadic AD and PD are unknown. It is now established that both AD and PD involve a systemic bioenergetic defect caused by specific lesions in the mitochondrial electron transport chain. The defects are primary (genetic), arising from mitochondrial DNA (mtDNA) and can be transferred from cell to cell through transfer of mtDNA. Transfer of mtDNA from AD or PD patient platelets into mtDNA-depleted human SY5Y neuroblastoma cells results in the creation of a model """"""""neuron"""""""" in which genetic, biochemical, and cellular features of the AD and PD phenotypes can be studied. This program consists of four projects. These projects will use this novel method to characterize further the mitochondrial genetic abnormalities in AD and PD mtDNA, to quantitate intracellular mitochondrial turnover and """"""""trafficking"""""""" of both normal and impaired mitochondria, to study the role of mitochondrial failure in neurodegeneration, the relationships between oxygen radicals and apoptosis in neurodegeneration, the effects of mitochondrial abnormalities on neuronal calcium metabolism, and the molecular mechanisms of neurotrophin action and control of cell death pathways. This program will further characterize involvement of the mitochondrial genome in both AD and PD and will strengthen a hypothesis about the primary pathogenic factor in each disorder-a hypothesis which can be directly tested through sequencing of mtDNA. Establishment of primary involvement of mtDNA in AD and PD will also provide new therapeutic opportunities aimed at modifying dysfunction or dealing with consequences such as oxygen radical production. This program will also develop an excellent model system for investigation of therapeutic maneuvers. The four Projects will be supported by a Molecular Biochemical and Anatomical Cell Culture Core Laboratory and an Administrative Core. The Program will receive regular oversight by an Internal Advisory Committee and through use of three external consultants per year.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Application #
Study Section
Special Emphasis Panel (ZAG1-PCR-5 (O1))
Program Officer
Snyder, D Stephen
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University of Virginia
Schools of Medicine
United States
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Trimmer, Patricia A; Bennett Jr, James P (2009) The cybrid model of sporadic Parkinson's disease. Exp Neurol 218:320-5
Thiffault, Christine; Bennett Jr, James P (2005) Cyclical mitochondrial deltapsiM fluctuations linked to electron transport, F0F1 ATP-synthase and mitochondrial Na+/Ca+2 exchange are reduced in Alzheimer's disease cybrids. Mitochondrion 5:109-19
Onyango, Isaac G; Tuttle, Jeremy B; Bennett Jr, James P (2005) Altered intracellular signaling and reduced viability of Alzheimer's disease neuronal cybrids is reproduced by beta-amyloid peptide acting through receptor for advanced glycation end products (RAGE). Mol Cell Neurosci 29:333-43
Trimmer, Patricia A; Borland, M Kathleen (2005) Differentiated Alzheimer's disease transmitochondrial cybrid cell lines exhibit reduced organelle movement. Antioxid Redox Signal 7:1101-9
Onyango, Isaac G; Tuttle, Jeremy B; Bennett Jr, James P (2005) Brain-derived growth factor and glial cell line-derived growth factor use distinct intracellular signaling pathways to protect PD cybrids from H2O2-induced neuronal death. Neurobiol Dis 20:141-54
Onyango, Isaac G; Bennett Jr, James P; Tuttle, Jeremy B (2005) Endogenous oxidative stress in sporadic Alzheimer's disease neuronal cybrids reduces viability by increasing apoptosis through pro-death signaling pathways and is mimicked by oxidant exposure of control cybrids. Neurobiol Dis 19:312-22
Onyango, Isaac G; Tuttle, Jeremy B; Bennett Jr, James P (2005) Activation of p38 and N-acetylcysteine-sensitive c-Jun NH2-terminal kinase signaling cascades is required for induction of apoptosis in Parkinson's disease cybrids. Mol Cell Neurosci 28:452-61
Trimmer, Patricia A; Keeney, Paula M; Borland, M Kate et al. (2004) Mitochondrial abnormalities in cybrid cell models of sporadic Alzheimer's disease worsen with passage in culture. Neurobiol Dis 15:29-39
Kindler, Dean D; Thiffault, Christine; Solenski, Nina J et al. (2003) Neurotoxic nitric oxide rapidly depolarizes and permeabilizes mitochondria by dynamically opening the mitochondrial transition pore. Mol Cell Neurosci 23:559-73
Dennis, Jameel; Bennett Jr, James P (2003) Interactions among nitric oxide and Bcl-family proteins after MPP+ exposure of SH-SY5Y neural cells II: exogenous NO replicates MPP+ actions. J Neurosci Res 72:89-97

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