Evaluating dendritic DJ-1 targets as a framework for identifying pharmacotherapies for TSC-related neurological disorders

PROJECT SUMMARY/ABSTRACT Epilepsy, autism spectrum disorder, and anxiety disorders are highly comorbid. Indeed, this is the case in TSC. Despite the importance of this problem, the molecular connection among these disorders are poorly understood. Importantly, pharmacological therapies that can mitigate these comorbid symptoms are lacking. Because of these medical needs, we are taking advantage of TSC as a model system to gain a better understanding of the mechanisms linking epilepsy, autism and anxiety disorders. The mammalian/mechanistic target of rapamycin (mTOR) is hyperactive in epilepsy, autism, anxiety disorders, and TSC. A kinase that regulates protein synthesis, our previous work has demonstrated that perturbations in mTOR greatly affects the levels of proteins at synapses—critical subcellular structures that mediate communication among neurons. Of note, these comorbid disorders manifest synaptic dysfunction. Moreover, we have discovered that mTOR equally induces and inhibits synaptic protein levels. Thus, chronic, overactive mTOR may perpetually keep synapses in a state of disease causing some proteins to be overexpressed and others to be underexpressed. Unlike the proteins that are overexpressed when mTOR is hyperactive, the identity of the underexpressed proteins and how their levels are regulated are relatively unknown. Insights into the mechanisms underlying the diminished expression of proteins when mTOR is hyperactive is essential to gain a better understanding of how these comorbid disorders are molecularly linked. We have recently found that mTOR controls the levels of synaptic DJ-1, a newly-identified RNA binding protein that represses the translation of its associated mRNAs. Thus, DJ-1 may mediate the underexpression of proteins at or near the synapse when mTOR is active. Two of these underexpressed proteins whose mRNAs associated with DJ-1 are CaV1.2 and alpha2delta2—L-type voltage-dependent calcium channel (L-VDCC) subunits implicated in epilepsy, autism and anxiety disorders. Using molecular and behavioral approaches, we will determine the mechanisms and impact of aberrant DJ- 1/L-VDCC pathway in mediating anxiety-like disorders and epilepsy in two mouse models of TSC. These studies will lay down a biological framework to delineate underlying mechanisms that may be shared among comorbid neurological and neuropsychiatric diseases, paving a way for potential treatments for epilepsy, autism, anxiety disorders and TSC. Our investigations on DJ-1 and its downstream targets may also offer a pathway that can be exploited to expand our tools and avenues in treating complex, neurological disorders. Lastly, these studies will develop and sustain research excellence of a new investigator at NC A&T State University, a Historically Black College and University, catalyze institutional research culture, and enrich the university’s research environment. Importantly, our proposed investigations will provide underserved graduate and undergraduate students in biomedical sciences with robust research opportunities, contributing to the development of a diverse scientific workforce.