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.
|Mills, Kelly A; Mari, Zoltan; Bakker, Catherine et al. (2016) Gait function and locus coeruleus Lewy body pathology in 51 Parkinson's disease patients. Parkinsonism Relat Disord 33:102-106|
|Mao, Xiaobo; Ou, Michael Tianhao; Karuppagounder, Senthilkumar S et al. (2016) Pathological Î±-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353:|
|Geiger, Joshua T; Arthur, Karissa C; Dawson, Ted M et al. (2016) C9orf72 Hexanucleotide Repeat Analysis in Cases with Pathologically Confirmed Dementia with Lewy Bodies. Neurodegener Dis 16:370-2|
|Mata, Ignacio F; Leverenz, James B; Weintraub, Daniel et al. (2016) GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord 31:95-102|
|Rosenthal, Liana S; Drake, Daniel; Alcalay, Roy N et al. (2016) The NINDS Parkinson's disease biomarkers program. Mov Disord 31:915-23|
|Jo, Junghyun; Xiao, Yixin; Sun, Alfred Xuyang et al. (2016) Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons. Cell Stem Cell 19:248-57|
|Karuppagounder, Senthilkumar S; Xiong, Yulan; Lee, Yunjong et al. (2016) LRRK2 G2019S transgenic mice display increased susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-mediated neurotoxicity. J Chem Neuroanat 76:90-97|
|Davis, Marie Y; Johnson, Catherine O; Leverenz, James B et al. (2016) Association of GBA Mutations and the E326K Polymorphism With Motor and Cognitive Progression in Parkinson Disease. JAMA Neurol 73:1217-1224|
|Nucifora Jr, Frederick C; Nucifora, Leslie G; Ng, Chee-Hoe et al. (2016) Ubiqutination via K27 and K29 chains signals aggregation and neuronal protection of LRRK2 by WSB1. Nat Commun 7:11792|
|Mills, Kelly A; Mari, Zoltan; Pontone, Gregory M et al. (2016) Cognitive impairment in Parkinson's disease: Association between patient-reported and clinically measured outcomes. Parkinsonism Relat Disord 33:107-114|
Showing the most recent 10 out of 206 publications