The overall goals of this proposal are to understand the role of a-synuclein, parkin, LRRK2 and the relationship with oxidative stress in the pathogenesis and pathology of Parkinson's disease (PD) and to define the molecular mechanisms of neuronal injury in animal models of PD. The program represents a multi-disciplinary, mechanistic approach involving interactive, productive investigators with complementary areas of expertise who have long been committed to the studies of neurodegenerative diseases.
Our aim will be to integrate the activities of various disciplines such that the interrelationships will result in greater scientific contributions and achievements if each project were pursued individually. The program has one major theme: To understand the role of familial associated genes a-synuclein, parkin and LRRK2 in the pathogenesis of Parkinson's disease and related disorders. The role of a-synuclein, parkin, LRRK2 and oxidative stress in PD pathogenesis will be investigated using molecular, transgenic, neuropathologic, cell biologic, and neurobehavioral approaches to examine the mechanism of neuronal dysfunction and injury due to alterations in these gene products. We believe that our multi-disciplinary approach has the capacity to produce unique information concerning the mechanisms of neurodegeneration in genetic animal models of Parkinson's disease and the related synucleinopathies and lead to better understanding of the function and the role of a-synuclein, parkin and LRRK2 in normal and pathophysiologic processes related to PD. The program consists of three projects: 1) Biology of Parkin and its Role in Parkinson's Disease;2) Mechanisms of Neurodegeneration in Human alpha-Synuclein Transgenic Mice;3) LRRK2 Biology in Parkinson's disease and four cores A) Administration and training, B) Bioenergetics, C) Transgenic and Neurobehavior and D) Clinical.
Parkinson's Disease (PD) is a common progressive neurodegenerative disorder with no neuroprotective or neurorestorative therapy. Understanding the molecular mechanisms by which a-synuclein, parkin, LRRK2 and oxidative stress contribute to the degeneration of neurons in PD could lead to innovative therapies to slow or halt the progression of PD.
|Martin, Ian; Kim, Jungwoo Wren; Dawson, Valina L et al. (2014) LRRK2 pathobiology in Parkinson's disease. J Neurochem 131:554-65|
|Dawson, Ted M; Dawson, Valina L (2014) Parkin plays a role in sporadic Parkinson's disease. Neurodegener Dis 13:69-71|
|Lee, Yun-Il; Giovinazzo, Daniel; Kang, Ho Chul et al. (2014) Protein microarray characterization of the S-nitrosoproteome. Mol Cell Proteomics 13:63-72|
|Siuda, Joanna; Jasinska-Myga, Barbara; Boczarska-Jedynak, Magdalena et al. (2014) Early-onset Parkinson's disease due to PINK1 p.Q456X mutation--clinical and functional study. Parkinsonism Relat Disord 20:1274-8|
|Fatokun, Amos A; Dawson, Valina L; Dawson, Ted M (2014) Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities. Br J Pharmacol 171:2000-16|
|Stafa, Klodjan; Tsika, Elpida; Moser, Roger et al. (2014) Functional interaction of Parkinson's disease-associated LRRK2 with members of the dynamin GTPase superfamily. Hum Mol Genet 23:2055-77|
|Martin, Ian; Kim, Jungwoo Wren; Lee, Byoung Dae et al. (2014) Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease. Cell 157:472-85|
|Tsika, Elpida; Glauser, Liliane; Moser, Roger et al. (2014) Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. Hum Mol Genet 23:4621-38|
|Pirooznia, Sheila K; Dawson, Valina L; Dawson, Ted M (2014) Motor neuron death in ALS: programmed by astrocytes? Neuron 81:961-3|
|Lasagna-Reeves, Cristian A; Sengupta, Urmi; Castillo-Carranza, Diana et al. (2014) The formation of tau pore-like structures is prevalent and cell specific: possible implications for the disease phenotypes. Acta Neuropathol Commun 2:56|
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