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.
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.
|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|
|Grosso, Hilary; Woo, Jong-Min; Lee, Kang-Woo et al. (2014) Transglutaminase 2 exacerbates ?-synuclein toxicity in mice and yeast. FASEB J 28:4280-91|
|Potts, Lisa F; Wu, Hao; Singh, Arun et al. (2014) Modeling Parkinson's disease in monkeys for translational studies, a critical analysis. Exp Neurol 256:133-43|
|Uthayathas, Subramaniam; Masilamoni, Gunasingh J; Shaffer, Christopher L et al. (2014) Phosphodiesterase 10A inhibitor MP-10 effects in primates: comparison with risperidone and mechanistic implications. Neuropharmacology 77:257-67|
|Choi, Doo Chul; Chae, Yoon-Jee; Kabaria, Savan et al. (2014) MicroRNA-7 protects against 1-methyl-4-phenylpyridinium-induced cell death by targeting RelA. J Neurosci 34:12725-37|
|Lee, Kang-Woo; Im, Joo-Young; Woo, Jong-Min et al. (2013) Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease. Neurotherapeutics 10:143-53|
|Uthayathas, Subramaniam; Shaffer, Christopher L; Menniti, Frank S et al. (2013) Assessment of adverse effects of neurotropic drugs in monkeys with the "drug effects on the nervous system" (DENS) scale. J Neurosci Methods 215:97-102|
|Braithwaite, Steven P; Stock, Jeffry B; Mouradian, M Maral (2012) ýý-Synuclein phosphorylation as a therapeutic target in Parkinson's disease. Rev Neurosci 23:191-8|
|Grosso, Hilary; Mouradian, M Maral (2012) Transglutaminase 2: biology, relevance to neurodegenerative diseases and therapeutic implications. Pharmacol Ther 133:392-410|
|Mouradian, M Maral (2012) MicroRNAs in Parkinson's disease. Neurobiol Dis 46:279-84|