Parkinson's disease (PD) is a late-onset, progressive motor disease marked by relatively selective nigrostrial dopaminergic degradation. Recent studies showed a link between PD and deficiency of the mitochondrial NADH dehydrogenase (complex I). It has been demonstrated that administration of agents that cause complex I inhibition (such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone) induces PD-like symptoms in primates or rodents. It is, therefore, anticipated that relieving dopaminergic cells of harmful effects caused by the dysfunction of complex I may provide a novel remedy for PD. Mitochondria of Baker's yeast, Saccharomyces cerevisiae, lack complex I but instead has the rotenone-insensitive NADH dehydrogenase (Ndi1). The applicants have shown that Ndi1 restores respiratory function to complex I-deficient mammalian cells and renders the respiratory chain resistant to complex I inhibitors. In addition, Ndi1 has been successfully introduced into dopaminergic nerve rat PC12 and mouse MN9D cells without impairing their capability of differentiation. In this proposal, the applicants will employ the Ndi1 enzyme as a therapeutic tool to retard PD and investigate its potential using animal models for PD. The studies during this grant term are as follows: (1) Refinement of the optimum conditions of the Ndi1 expression in nigral dopaminergic neurons of rodents. (2) Suppression of PD's disease like symptoms in rodent models by the Ndi1 expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048441-04
Application #
7340442
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Sutherland, Margaret L
Project Start
2005-01-01
Project End
2008-12-31
Budget Start
2008-01-01
Budget End
2008-12-31
Support Year
4
Fiscal Year
2008
Total Cost
$290,858
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Marella, Mathieu; Seo, Byoung Boo; Nakamaru-Ogiso, Eiko et al. (2008) Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease. PLoS One 3:e1433
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Escobar-Khondiker, Myriam; Hollerhage, Matthias; Muriel, Marie-Paule et al. (2007) Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons. J Neurosci 27:7827-37
Seo, Byoung Boo; Marella, Mathieu; Yagi, Takao et al. (2006) The single subunit NADH dehydrogenase reduces generation of reactive oxygen species from complex I. FEBS Lett 580:6105-8
Yagi, Takao; Seo, Byoung Boo; Nakamaru-Ogiso, Eiko et al. (2006) Can a single subunit yeast NADH dehydrogenase (Ndi1) remedy diseases caused by respiratory complex I defects? Rejuvenation Res 9:191-7
Seo, Byoung Boo; Nakamaru-Ogiso, Eiko; Flotte, Terence R et al. (2006) In vivo complementation of complex I by the yeast Ndi1 enzyme. Possible application for treatment of Parkinson disease. J Biol Chem 281:14250-5

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