Like most neurodegenerative disorders, Parkinson's disease (PD) has as its pathological hallmark specific degeneration of certain neuronal subtypes. Specifically, dopamine neurons in the substantia nigra (SN) are exquisitely sensitive to damage in human PD and in animal models of PD, such as administration of the mitochondrial complex I poison rotenone (a common pesticide) to rats. This is in contrast to the relative resistance of other types of neurons. The molecular underpinnings for this selective neuronal vulnerability are unknown. Since inhibition of mitochondrial metabolism by rotenone recapitulates behavioral signs and neuropathological findings of PD, we hypothesize that differences in energy metabolism between susceptible and resistant neurons might underlie differential vulnerability. In the current proposal, we will: (1) evaluate the metabolic transcriptional response to complex I inhibition; (2) test the acute regulation of energy metabolism in dopamine neurons; and (3) determine if modulation of energy metabolism is protective in an in vitro model of PD. These experiments will provide a detailed understanding of mitochondrial energy metabolism in dopamine neurons and give insight into the pathogenesis and potential treatment of PD. The research outlined above is part of a customized five-year plan of training and career development for the Principal Investigator. The proposal includes active mentoring by experienced scientists, access to diverse resources, and an environment uniquely suited to help the PI develop as an independent physician scientist.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08NS048858-01A1
Application #
6918915
Study Section
NST-2 Subcommittee (NST)
Program Officer
Oliver, Eugene J
Project Start
2005-07-01
Project End
2010-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$167,465
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Annerino, Dana M; Arshad, Shawn; Taylor, Georgia M et al. (2012) Parkinson's disease is not associated with gastrointestinal myenteric ganglion neuron loss. Acta Neuropathol 124:665-80
Greene, James G (2012) Current status and future directions of gene expression profiling in Parkinson's disease. Neurobiol Dis 45:76-82
Noorian, Ali Reza; Taylor, Georgia M; Annerino, Dana M et al. (2011) Neurochemical phenotypes of myenteric neurons in the rhesus monkey. J Comp Neurol 519:3387-401
Anitha, Mallappa; Shahnavaz, Nikrad; Qayed, Emad et al. (2010) BMP2 promotes differentiation of nitrergic and catecholaminergic enteric neurons through a Smad1-dependent pathway. Am J Physiol Gastrointest Liver Physiol 298:G375-83
Greene, James G; Dingledine, Raymond; Greenamyre, J Timothy (2010) Neuron-selective changes in RNA transcripts related to energy metabolism in toxic models of parkinsonism in rodents. Neurobiol Dis 38:476-81
Greene, James G; Borges, Karin; Dingledine, Raymond (2009) Quantitative transcriptional neuroanatomy of the rat hippocampus: evidence for wide-ranging, pathway-specific heterogeneity among three principal cell layers. Hippocampus 19:253-64
Greene, James G; Noorian, Ali Reza; Srinivasan, Shanthi (2009) Delayed gastric emptying and enteric nervous system dysfunction in the rotenone model of Parkinson's disease. Exp Neurol 218:154-61
Greene, J G; Greenamyre, J T; Dingledine, R (2008) Sequential and concerted gene expression changes in a chronic in vitro model of parkinsonism. Neuroscience 152:198-207
Hamill, Cecily E; Caudle, W Michael; Richardson, Jason R et al. (2007) Exacerbation of dopaminergic terminal damage in a mouse model of Parkinson's disease by the G-protein-coupled receptor protease-activated receptor 1. Mol Pharmacol 72:653-64
Anderson, Grant; Noorian, Ali Reza; Taylor, Georgia et al. (2007) Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease. Exp Neurol 207:4-12

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