Parkinson's disease (PD) is the second most common and debilitating age-associated human neurodegenerative disorder. Clinically, PD is characterized by tremor, slowness of movement, stiffness, and postural instability. Pathologically, it is indicated by activation of glial cells and progressive degeneration of the nigrostriatal dopaminergic neurons associated with the presence of intracytoplasmic inclusions (Lewy bodies). This application addresses an important aspect of PD. Although the rate of disease progression varies from patient to patient, PD is a progressive neurodegenerative disorder. However, the mechanism behind disease progression is poorly understood. We hypothesize that RANTES and eotaxin could hold the key for driving disease progression and that targeting these two chemokines may be an important strategy to control T cell infiltration and hence the disease progression in PD. Here this hypothesis will be tested from several experiments on mice, monkeys and humans. It is known that nigrostriatal pathology does not persist in acute MPTP mouse model.
Under Specific aim I, we will investigate if supplementation of RANTES and eotaxin induces persistent and progressive disease in acute MPTP-intoxicated mice.
Specific aim II has been planned to determine whether PD patients have higher levels of RANTES and eotaxin by monitoring the level of these two chemokines in serum of PD patients and age-matched controls. Finally, we have devoted the Specific aim III to delineate if blocking the functions of RANTES and eotaxin by maraviroc, an inhibitor of CCR5 and a FDA- approved drug, halt the disease progression in hemiparkinsonian monkeys. A positive outcome of this study will establish RANTES and eotaxin as targets for PD, translate CCR5-based treatment (maraviroc) to PD clinic, uncover the clue for the progression of PD, and find a drug to stop the progression of PD.
Parkinson's disease (PD) is a progressive neurodegenerative disorder. However, the mechanism behind disease progression is poorly understood. Here we will test the hypothesis that RANTES and eotaxin are key chemokines for driving disease progression and that targeting these two chemokines may be an important strategy to control the disease progression in PD. A positive outcome of this study will establish RANTES and eotaxin as targets for PD, translate CCR5-based treatment (maraviroc) to PD clinic, uncover the clue for the progression of PD, and find a drug to stop the progression of PD.
|Rangasamy, Suresh B; Dasarathi, Sridevi; Pahan, Priyanka et al. (2018) Low-Dose Aspirin Upregulates Tyrosine Hydroxylase and Increases Dopamine Production in Dopaminergic Neurons: Implications for Parkinson's Disease. J Neuroimmune Pharmacol :|
|Kundu, Madhuchhanda; Roy, Avik; Pahan, Kalipada (2017) Selective neutralization of IL-12 p40 monomer induces death in prostate cancer cells via IL-12-IFN-?. Proc Natl Acad Sci U S A 114:11482-11487|
|Chandra, Goutam; Roy, Avik; Rangasamy, Suresh B et al. (2017) Induction of Adaptive Immunity Leads to Nigrostriatal Disease Progression in MPTP Mouse Model of Parkinson's Disease. J Immunol 198:4312-4326|
|Roy, Avik; Rangasamy, Suresh Babu; Kundu, Madhuchhanda et al. (2016) BPOZ-2 Gene Delivery Ameliorates Alpha-Synucleinopathy in A53T Transgenic Mouse Model of Parkinson's Disease. Sci Rep 6:22067|
|Litvan, Irene; Lees, Peter S J; Cunningham, Christopher R et al. (2016) Environmental and occupational risk factors for progressive supranuclear palsy: Case-control study. Mov Disord 31:644-52|
|Roy, Avik; Kundu, Madhuchhanda; Jana, Malabendu et al. (2016) Identification and characterization of PPAR? ligands in the hippocampus. Nat Chem Biol 12:1075-1083|
|O'Keefe, Joan A; Robertson-Dick, Erin E; Hall, Deborah A et al. (2016) Gait and Functional Mobility Deficits in Fragile X-Associated Tremor/Ataxia Syndrome. Cerebellum 15:475-82|
|Chandra, Goutam; Rangasamy, Suresh B; Roy, Avik et al. (2016) Neutralization of RANTES and Eotaxin Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson Disease. J Biol Chem 291:15267-81|
|Bera, Swapna; Kar, Rajiv K; Mondal, Susanta et al. (2016) Structural Elucidation of the Cell-Penetrating Penetratin Peptide in Model Membranes at the Atomic Level: Probing Hydrophobic Interactions in the Blood-Brain Barrier. Biochemistry 55:4982-96|
|Brody, David M; Litvan, Irene; Warner, Steve et al. (2016) Relationship between uric acid levels and progressive supranuclear palsy. Mov Disord 31:663-7|
Showing the most recent 10 out of 18 publications