Increasing evidence implicates mitochondrial dysfunction in the pathogenesis of Parkinson's disease (PD): on average, PD patients have a modest, systemic defect in complex I activity;one causative gene encodes a mitochondrial kinase (PINKi);two other causative genes encode proteins (parkin &DJ-i) that traffic in and out of mitochondria;and systemic inhibition of mitochondria] function accurately reproduces many features of PD. This program brings together 4 established investigators - Tim Greenamyre, Jun Chen, Valerian Kagan and Teresa Hastings - who are each individually interested in the pathogenesis of PD and the roles that mitochondria play in this disorder. Moreover, the director of this program's neuropathology core, Charleen Chu, also has an interest and track record in mitochondria and PD. Greenamyre (Project 1) will study how iron accumulates in PD via a novel pathway mediated by transferrin and a previously unrecognized mitochondrial transferrin receptor (TfR2) that is selectively localized in substantia nigra dopaminergic neurons. Kagan (Project 2) is studying mechanisms and consequences of the interactions of alpha-synuclein with cytochrome c via binding to the mitochondrial anionic phospholipid, cardiolipin. This complex of alphasynuclein-cardiolipin-cytochrome c may prevent apoptosome formation while also promoting oxidative stress via a novel peroxidase activity. Chen (Project 3) will study mechanisms and relevance of HSP27 translocation to mitochondria and the ASKi/JNK apoptotic pathway in PD. Hastings (Project 4) will study the roles of mitochondrial selenoproteins, such as glutathione peroxidase 4 and thioredoxin reductase 2, in neurodegeneration in PD. The individual projects are supported by 2 scientific cores. The Molecular Core (Guodong Cao) will assist each project with design and production of constructs for gene overexpression or gene silencing, generation of transient and stable transfections, and production of viral vectors for in vivo gene transfer. As pathogenic mechanisms are defined in model systems in Projects 1-4, their relevance will be confirmed in postmortem human tissue in collaboration with the Neuropathology Core (Charleen Chu). The overall Program is unified and strengthened by (i) numerous scientific interactions between the projects;(ii) the use of a common set of in vitro and in vivo model systems;and (iii) the scientific cores, which will be used by each project.

Public Health Relevance

As the second most common neurodegenerative disorder, PD affects 1.5 million individuals in the United States. The cause of neurodegeneration in PD is uncertain, but mitochondrial impairment has been strongly implicated. This Program will determine the roles of mitochondrial proteins in causing neurodegeneration, and each project will test novel therapeutic concepts designed to slow or stop the disease process.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Sutherland, Margaret L
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University of Pittsburgh
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Verma, Manish; Callio, Jason; Otero, P Anthony et al. (2017) Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants. J Neurosci 37:11151-11165
Di Maio, Roberto; Barrett, Paul J; Hoffman, Eric K et al. (2016) ?-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Sci Transl Med 8:342ra78
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Tapias, Victor; Greenamyre, J Timothy (2014) A rapid and sensitive automated image-based approach for in vitro and in vivo characterization of cell morphology and quantification of cell number and neurite architecture. Curr Protoc Cytom 68:12.33.1-22
Sanders, Laurie H; McCoy, Jennifer; Hu, Xiaoping et al. (2014) Mitochondrial DNA damage: molecular marker of vulnerable nigral neurons in Parkinson's disease. Neurobiol Dis 70:214-23
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