Development of therapies to retard Parkinson's disease

Summary

Principal Investigator: Takao Yagi
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2005-01-01 - 2008-12-31
more information: NIH RePORT

Top Publications

  1. ncbi The single subunit NADH dehydrogenase reduces generation of reactive oxygen species from complex I
    Byoung Boo Seo
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    FEBS Lett 580:6105-8. 2006
  2. pmc Neuroprotective effect of long-term NDI1 gene expression in a chronic mouse model of Parkinson disorder
    Jennifer Barber-Singh
    The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California 92037, USA
    Rejuvenation Res 12:259-67. 2009
  3. pmc Parkinson's disease and mitochondrial complex I: a perspective on the Ndi1 therapy
    Mathieu Marella
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
    J Bioenerg Biomembr 41:493-7. 2009
  4. pmc Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease
    Mathieu Marella
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
    PLoS ONE 3:e1433. 2008
  5. ncbi Mechanism of cell death caused by complex I defects in a rat dopaminergic cell line
    Mathieu Marella
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 282:24146-56. 2007
  6. ncbi Obligatory role for complex I inhibition in the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
    Jason R Richardson
    Department of Environmental and Occupational Medicine, University of Medicine and Dentistry, New Jersey Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854, USA
    Toxicol Sci 95:196-204. 2007
  7. ncbi Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons
    Myriam Escobar-Khondiker
    Experimental Neurology, Philipps University, D 35033 Marburg, Germany
    J Neurosci 27:7827-37. 2007
  8. ncbi Can a single subunit yeast NADH dehydrogenase (Ndi1) remedy diseases caused by respiratory complex I defects?
    Takao Yagi
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Reseach Institute, La Jolla, California 92037, USA
    Rejuvenation Res 9:191-7. 2006
  9. ncbi Possibility of transkingdom gene therapy for complex I diseases
    Takao Yagi
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
    Biochim Biophys Acta 1757:708-14. 2006
  10. ncbi In vivo complementation of complex I by the yeast Ndi1 enzyme. Possible application for treatment of Parkinson disease
    Byoung Boo Seo
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 281:14250-5. 2006

Detail Information

Publications11

  1. ncbi The single subunit NADH dehydrogenase reduces generation of reactive oxygen species from complex I
    Byoung Boo Seo
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    FEBS Lett 580:6105-8. 2006
    ..Furthermore, mitochondria from the NDI1-transduced cells showed a suppressed rate of ROS formation by the complex I inhibitors. We conclude that the Ndi1 enzyme is able to suppress ROS overproduction from defective complex I...
  2. pmc Neuroprotective effect of long-term NDI1 gene expression in a chronic mouse model of Parkinson disorder
    Jennifer Barber-Singh
    The Scripps Research Institute, Department of Molecular and Experimental Medicine, La Jolla, California 92037, USA
    Rejuvenation Res 12:259-67. 2009
    ..The data presented in this study demonstrate a protective effect of the NDI1 gene in dopaminergic neurons, suggesting its therapeutic potential for Parkinson-like disorders...
  3. pmc Parkinson's disease and mitochondrial complex I: a perspective on the Ndi1 therapy
    Mathieu Marella
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
    J Bioenerg Biomembr 41:493-7. 2009
    ....
  4. pmc Protection by the NDI1 gene against neurodegeneration in a rotenone rat model of Parkinson's disease
    Mathieu Marella
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
    PLoS ONE 3:e1433. 2008
    ..The present study shows, for the first time, the powerful neuroprotective effect offered by the Ndi1 enzyme in a rotenone rat model of PD...
  5. ncbi Mechanism of cell death caused by complex I defects in a rat dopaminergic cell line
    Mathieu Marella
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 282:24146-56. 2007
    ..Under these conditions, ROS formation by complex I is known to be minimal. Possible use of our cellular model is discussed with regard to development of therapeutic strategies for neurodegenerative diseases caused by complex I defects...
  6. ncbi Obligatory role for complex I inhibition in the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
    Jason R Richardson
    Department of Environmental and Occupational Medicine, University of Medicine and Dentistry, New Jersey Robert Wood Johnson Medical School and Environmental and Occupational Health Sciences Institute, Piscataway, New Jersey 08854, USA
    Toxicol Sci 95:196-204. 2007
    ..Furthermore, combined with reports of a complex I defect in Parkinson's disease (PD) patients, the present study affirms the utility of MPTP in understanding the molecular mechanisms underlying dopaminergic neurodegeneration in PD...
  7. ncbi Annonacin, a natural mitochondrial complex I inhibitor, causes tau pathology in cultured neurons
    Myriam Escobar-Khondiker
    Experimental Neurology, Philipps University, D 35033 Marburg, Germany
    J Neurosci 27:7827-37. 2007
    ....
  8. ncbi Can a single subunit yeast NADH dehydrogenase (Ndi1) remedy diseases caused by respiratory complex I defects?
    Takao Yagi
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Reseach Institute, La Jolla, California 92037, USA
    Rejuvenation Res 9:191-7. 2006
    ..The Ndi1 protein has a great potential as a molecular remedy for complex I deficiencies...
  9. ncbi Possibility of transkingdom gene therapy for complex I diseases
    Takao Yagi
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
    Biochim Biophys Acta 1757:708-14. 2006
    ..The use of NDI1 as a potential molecular therapy for complex I-deficient diseases is briefly discussed, including the proposed animal model...
  10. ncbi In vivo complementation of complex I by the yeast Ndi1 enzyme. Possible application for treatment of Parkinson disease
    Byoung Boo Seo
    Division of Biochemistry, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 281:14250-5. 2006
    ..These results indicate that the expressed Ndi1 protein elicits resistance to MPTP-induced neuronal injury. The present study is the first successful demonstration of complementation of complex I by the Ndi1 enzyme in animals...
  11. pmc Successful amelioration of mitochondrial optic neuropathy using the yeast NDI1 gene in a rat animal model
    Mathieu Marella
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
    PLoS ONE 5:e11472. 2010
    ..Establishment of animal models of LHON should help elucidate mechanism of the disease and could be utilized for possible development of therapeutic strategies...