Striatal Conductors of   Motor Abnormalities 

Everyday motor functions such as walking and running, playing tennis, or pedaling a bicycle, are energy consuming processes, controlled by the brain circuits. The striatum, which is comprised of D1R-positive MSNs (also known as a direct pathway) and D2R-positive MSNs (indirect pathway), is central to this complex circuitry and relays signals to and from major parts of the brain. MSN dysfunction can lead to the motor abnormalities seen in HD and PD. The striatum is also the main site of action for many clinically approved drugs, such as l-DOPA and haloperidol, to treat psychiatric and neurological diseases. However, despite many advances, the precise striatal signaling mechanisms that regulate motor functions in the striatum remain unclear. 

 

Despite striatal involvement in regulating motor behavior being well-established, the underlying molecular mechanisms remain not fully understood. In our planned research, we are interested in understanding the D1R-MSN and D2R-MSN specific inhibitory function and Rhesactome protein complexes of Rhes. As Rhes is highly enriched in the synaptic fractions, we are particularly interested in deciphering the role of synapse vs. non-synaptic protein complexes and the underlying mechanisms by which they diminish motor activity, by biochemical and gene knockout strategies. Such studies may aid the development of novel approaches and intracellular “signalosomes” targets to treat various neurological and psychological disorders associated with striatal dysfunction (Fig. 2).

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We are interested in the D1R- and D2R-specific roles of RasGRP1 in orchestrating LID (L-DOPA-induced dyskinesia). For example, LID induces morphological changes in both D1R and D2R MSN. We found RasGRP1 is upregulated in D1R-MSN, and we will determine whether RasGRP1 effects D1R and D2R changes in LID. Based on previous studies, we propose to test E2F-1, which is upregulated in the LID striatum (unpublished), as a potential regulator of RasGRP1 and LID. As H-Ras and RHEB are spatially separated in the striatum, we will identify distinct RasGRP1/GTPase complexes that may regulate ERK and mTOR signaling in a spatially compartmentalized manner in the MSNs under LID (Fig. 2).

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We will generate D1R/D2R-specific deletion of Raptor and D1R/D2R-specific deletion of Rictor for systematic assessment of the MSN cell type-specific role(s) in striatal motor functions.  We found, using LC/MS/MS, several novel binding partner of mTOR in the brain, such as ATP5B, Mic60, Uqcrc1/2, Slc25a3, Ndufs1, PDH-E1, and Cox6c, that bound to mTOR, at an abundance equivalent to the established mTORC1-binding partner, PRAS40. We are interested in understanding the molecular link between mitochondria, mTOR and motor activity in the brain.