Role of CaDAG-GEFI in striatal adaptionsof Parkinson's disease models

Project: Research project

Project Details


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 date7/1/1411/30/18


  • William N. & Bernice E. Bumpus Foundation (Agmt. Signed 6/26/14)


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