In Parkinson’s disease (PD), degeneration of dopaminergic neurons in the substantia nigra causes dopamine (DA) depletion in the striatum, the principal input structure of basal ganglia-thalamo-cortical network. In the initial stages of the disease, motor symptoms are effectively treated with a DA precursor, L-3,4- dihydroxyphenylalanine (L-DOPA). However, as the disease progresses and the dose of L-DOPA needed to achieve symptomatic benefit rises, severe motor complications develop, including abnormal involuntary movements (dyskinesia) and fluctuations in motor function. Although several theories have been proposed, the underlying mechanism of the L-DOPA-induced dyskinesia (LID) is not well understood. Moreover, the only LID treatment currently available (i.e. amantadine) is far from ideal. In both PD and LID states, neurons in the striatum undergo substantial adaptations that are likely to influence disease symptoms and LID. Here I seek to understand the molecular mechanisms underlying these striatal adaptations. I will focus on CalDAG-GEFI, a striatum-enriched signaling molecule whose downregulation is closely correlated with the severity of LID, and examine its role in the adaptive changes during PD and LID. Our studies will distinguish between the two major populations of principal striatal neuron: spiny projection neurons (SPNs). Adaptations in indirect pathway SPNs (iSPNs) have been strongly implicated in the PD state, whereas adaptations in direct pathway SPNs (dSPNs) have been implicated in LID.
|Effective start/end date||7/1/14 → 11/30/18|
- William N. & Bernice E. Bumpus Foundation (Agmt. Signed 6/26/14)
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