This project addresses one of the most disabling complications of dopaminergic therapy in Parkinson's disease, namely the development of involuntary movements named dyskinesias. The mechanisms underlying dyskinesias remain unknown, and we lack specific and effective treatments to eradicate them. Studies in animal models have shown that the striatal levels of the chronic transcription factor (FosB consistently increase during chronic levodopa treatment. Therefore, it has been hypothesized that (FosB may regulate the genes responsible for altered responses to dopaminergic drugs. Here, we will test the effects of the transgenic manipulation of (FosB protein expression in non-human primates. The novel approach taken in this project may address pathophysiologic aspects and help develop new therapies. The project includes three specific aims. In the first aim, we will assess the behavioral and molecular changes following the overexpression of (FosB in the striatum of parkinsonian monkeys using a viral vector- mediated gene delivery.
The second aim will examine the basal ganglia circuitry of these animals using electrophysiologic recordings and correlate them with the development of dyskinesias. And the third aim will confirm the role of (FosB by down-regulating the expression of the endogenous gene in rats and monkeys. This project employs diverse experimental approaches across disciplines to address an important health problem. From the construction of viral vectors, to the in vitro testing, to the final evaluations of motor behavior and physiologic correlates in primates, this sequence of translational studies is designed to establish the mechanistic role of (FosB in the development of dyskinesias. Furthermore, these studies will assess the clinical application of (FosB gene silencing as a therapeutic strategy in complicated Parkinson's disease.

Public Health Relevance

One of the most disabling complications of dopaminergic therapy in Parkinson's disease is the development of involuntary movements named dyskinesias. The mechanisms underlying dyskinesias remain unknown, and we lack specific and effective treatments to eradicate them. This project is focused on the changes in gene expression within the brain that are associated with chronic drug therapy and lead to the development of dyskinesias. The goals of the project are to elucidate the mechanisms of dyskinesias and to test a novel therapy using gene silencing technologies in non-human primates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS073994-01A1
Application #
8232567
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sieber, Beth-Anne
Project Start
2011-09-01
Project End
2016-07-31
Budget Start
2011-09-01
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$505,150
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Chen, Guiqin; Nie, Shuke; Han, Chao et al. (2017) Antidyskinetic Effects of MEK Inhibitor Are Associated with Multiple Neurochemical Alterations in the Striatum of Hemiparkinsonian Rats. Front Neurosci 11:112
Oh, Stephanie E; Mouradian, M Maral (2017) Regulation of Signal Transduction by DJ-1. Adv Exp Med Biol 1037:97-131
Phukan, Geetika; Shin, Tae Hwan; Shim, Jeom Soon et al. (2016) Silica-coated magnetic nanoparticles impair proteasome activity and increase the formation of cytoplasmic inclusion bodies in vitro. Sci Rep 6:29095
Singh, Arun; Mewes, Klaus; Gross, Robert E et al. (2016) Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease. Proc Natl Acad Sci U S A 113:9629-34
Park, Hye-Jin; Lee, Kang-Woo; Park, Eun S et al. (2016) Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies. Ann Clin Transl Neurol 3:769-780
Masilamoni, Gunasingh J; Uthayathas, Subramanian; Koenig, Gerhard et al. (2016) Effects of a novel phosphodiesterase 10A inhibitor in non-human primates: A therapeutic approach for schizophrenia with improved side effect profile. Neuropharmacology 110:449-457
Aung, Latt Latt; Mouradian, M Maral; Dhib-Jalbut, Suhayl et al. (2015) MMP-9 expression is increased in B lymphocytes during multiple sclerosis exacerbation and is regulated by microRNA-320a. J Neuroimmunol 278:185-9
Chaudhuri, Amrita Datta; Kabaria, Savan; Choi, Doo Chul et al. (2015) MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium-induced Cell Death. J Biol Chem 290:12425-34
Potts, Lisa F; Uthayathas, Subramaniam; Greven, Alexander C M et al. (2015) A new quantitative rating scale for dyskinesia in nonhuman primates. Behav Pharmacol 26:109-16
Singh, Arun; Liang, Li; Kaneoke, Yoshiki et al. (2015) Dopamine regulates distinctively the activity patterns of striatal output neurons in advanced parkinsonian primates. J Neurophysiol 113:1533-44

Showing the most recent 10 out of 27 publications