Parkinson's disease (PD) is a debilitating disorder resulting in severe motor dysfunction caused by progressive degeneration of the substantia nigra dopaminergic neurons. L-dihydroxyphenylalanine (L-DOPA) therapy alleviates the motor symptoms, however the utility of this agent for chronic treatment is limited due to the occurrence of abnormal involuntary movements known as dyskinesia. An understanding of how L-DOPA modulates signaling pathways in the striatum of PD is important in devising an effective treatment for L-DOPA induced dyskinesia (LID). Among the signaling molecules associated with LID is extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK) whose activation in medium spiny neurons has been associated with induction of LID. Preliminary results from our laboratory have shown that ERK is mainly activated in striatal cholinergic neurons with long-term administration of L-DOPA and is correlated with expression of LID. The objective of the proposed studies is to determine the functional significance of ERK activation in striatal cholinergic neurons with respect to the expression of LID. We will examine this issue in aphakia mice, a genetic model of nigrostriatal degeneration that expresses LID, as well as in established unilateral neurotoxin- lesion based models. The proposed experiments are focused on the following objectives: 1) Correlation of the temporal expression of dyskinesia with ERK activation in striatal cholinergic neurons;2) Characterization of the DA receptor subtype and intracellular signaling pathways linked to L-DOPA-induced ERK activation in striatal cholinergic neurons and medium spiny neurons;and 3) Determining the functional outcome of ERK activation in cholinergic neurons with respect to neuronal excitability and cholinergic phenotypic expression. A better understanding of cell signaling mechanisms involved in LID will facilitate identification of potential targets for the treatment of PD.
L-DOPA is the most efficacious drug therapy for Parkinson's disease (PD), but chronic administration of this drug leads to debilitating abnormal involuntary movements known as dyskinesia. Establishment of experimental models which can mimic the cellular and behavioral processes underlying PD and the development of L-DOPA-induced dyskinesia are important for developing alternative efficacious therapies without unwanted dyskinetic side effects. The research proposed here will provide insight with respect to cell signaling mechanisms involved in dyskinesia behavior and will facilitate identification of potential targets for the treatment of PD.
|Zhuang, Xiaoxi; Mazzoni, Pietro; Kang, Un Jung (2013) The role of neuroplasticity in dopaminergic therapy for Parkinson disease. Nat Rev Neurol 9:248-56|
|Kang, Un Jung; Auinger, Peggy; Parkinson Study Group ELLDOPA Investigators (2012) Activity enhances dopaminergic long-duration response in Parkinson disease. Neurology 78:1146-9|
|Ding, Yunmin; Won, Lisa; Britt, Jonathan P et al. (2011) Enhanced striatal cholinergic neuronal activity mediates L-DOPA-induced dyskinesia in parkinsonian mice. Proc Natl Acad Sci U S A 108:840-5|
|Beeler, Jeff A; Cao, Zhen Fang Huang; Kheirbek, Mazen A et al. (2010) Dopamine-dependent motor learning: insight into levodopa's long-duration response. Ann Neurol 67:639-47|