Tuberous sclerosis complex (TSC) is a human syndrome characterized by widespread development of benign tumors in multiple tissues, with lesions in the brain causing the most debilitating symptoms such as seizures and mental retardation. Germline mutations in either TSC1 or TSC2 tumor suppressor genes cause this syndrome. Recent genetic studies in Drosophila and biochemical studies in mammalian cells have suggested that TSC1 and TSC2 negatively regulate the target of rapamycin (TOR) signaling pathway to control cell growth. Abnormal activation of TOR signaling may thus underlie the pathogenesis of TSC and other benign tumor syndromes. TOR signaling appears to serve as a crucial integration point that coordinates cell growth and survival with energy and nutrient conditions. Little is known about the molecular mechanisms by which diverse environmental or physiological signals feed into the TSC/TOR signaling pathway to control cell growth and survival. In our preliminary studies of a Drosophila homologue of human DJ-1 gene, which is associated with familial Parkinson's disease, we have found that inhibition of DJ-1A leads to impaired TOR signaling and cell death and that DJ-1A genetically interacts with certain components of TSC/TOR pathway to promote cell survival. These results implicate DJ-1A as a novel regulator of TSC/TOR signaling. The goal of this proposal is to achieve a mechanistic understanding of the interaction between DJ-1A and the TSC/TOR pathway in promoting cell survival. The proposed genetic and biochemical analyses will provide novel insights into the regulation and function of TSC/TOR signaling. Further studies along this direction could solidify a fundamental role for TSC/TOR signaling in promoting cell survival under pathological conditions. These studies could implicate a common biochemical pathway in the pathogenesis of TSC and Parkinson's disease and offer one avenue for elucidating the molecular events that cause the development of brain lesions in TSC patients. Further studies could lead to the identification of new therapeutic targets and ultimately help develop rational mechanism-based treatment strategies that target TSC brain lesions. ? ? These studies could implicate a common pathway in the pathogenesis of TSC and Parkinson's disease. Further studies could lead to the identification of new therapeutic targets and ultimately help develop mechanism-based treatment strategies that target TSC brain lesions which cause the most devastating symptoms of the disease. ? ? ?
