mTOR is a multifunctional kinase involved in embryonic development, cancer, and diabetes. Its role and regulation in nervous system physiology and disease, however, remains less understood. This is a major problem, because the malfunction of mTOR activity (either high or low) has been linked to a variety of brain dysfunctions that affect a specific set of neuronal populations in the brain, such as epilepsy, mental retardation, Huntington's disease (HD), and Parkinson's disease (PD). A detailed understanding of how mTOR is regulated and what role it plays in selective brain regions is important for the development of better intervention strategies. Our long-term goal is to understand how striatum-enriched Rhes (Ras homolog-enriched in striatum) GTPase, which we found to activate mTOR (Subramaniam, 2012), can be manipulated in the striatum for preventive and therapeutic purposes. The objective here, which is the next step in pursuit of our goal, is to investigate the mechanisms by which Rhes GTPase regulates mTOR in cultured cells, and test the effect of mTOR deletion in the striatum on motor behaviors in vivo. Our central hypothesis is that Rhes GTPase is a major regulator of mTOR in the striatum, and that Rhes-mTOR circuitry controls striatal functions and dysfunctions. Our hypothesis has been formulated on the basis of our published data, demonstrating that Rhes GTPase, besides its role as a SUMO E3 ligase and regulator of striatal cell toxicity in HD, activates mTOR signaling, which mediates abnormal motor behaviors in PD. We propose to further confirm the mechanisms what regulates, and how, Rhes activates mTOR in the striatum. We will specifically address the following:
Aim 1 : Dissect the mechanisms of RasGRP1-Rhes circuitry in striatal mTORC1 activation;
Aim 2 : Identify the role of SUMOylation in Rhes-mediated mTORC1 activity;
and Aim 3 : Test the effect of striatal deletion of mTOR on mouse behavior and striatal pathology. Overall, our proposal is conceptually innovative as it combines multidisciplinary approaches- cell culture, animal models, biochemistry, pharmacology, cell signaling and behavior- to discover the striatal-specific role and regulation of Rhes-mTOR signaling. The results of this project will be significant, as it will advance our understanding of not on the fundamentals biology of striatal signaling and also help develop novel therapies and treatments for neurological disorders, such as HD and PD, which are associated with Rhes-mTOR dysfunctions.
The proposed work is relevant to public health because the discovery of striatal signaling mechanisms orchestrated by RasGRP1-Rhes-mTORC1 circuitry is ultimately expected to increase understanding of the pathogenesis associated with striatum, such as of Huntington disease and Parkinson disease, as well as provide framework for developing novel therapeutic strategies. Thus, the proposed research is relevant to the part of NIH's mission that pertains to acquiring basic insights that will aid to lessen the pain of human o disability.
|Shahani, Neelam; Huang, Wen-Chin; Varnum, Megan et al. (2017) Forebrain depletion of Rheb GTPase elicits spatial memory deficits in mice. Neurobiol Aging 50:134-143|
|Shahani, Neelam; Swarnkar, Supriya; Giovinazzo, Vincenzo et al. (2016) RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network (""Rhesactome"") in the striatum. Sci Signal 9:ra111|