Posted November 13, 2015

Overview | Animal Models | Signaling Pathways | Inflammation Mechanisms | Currently Active Research Projects

Note: Bolded hyperlinks will direct you to the investigators' public and technical abstracts, and publications, if applicable.

Dr. Bo Xiao (FY05; Johns Hopkins University) examined whether upregulation of Rheb signaling in TSC disturbs the balance between the excitatory glutamate and the inhibitory GABA transmission in the brain resulting in seizure activities in TSC. Findings from this research indicate that an increase in Rheb signaling could lead to neuronal death. This result provided critical insight into the mechanism underlying neuronal loss and seizure development in TSC brains and Rheb signaling regulation of AMPA-type glutamate receptors produced in the brain.

Dr. Yong-Jian Liu (FY05; University of Pittsburgh) investigated FKBP38, a known receptor for the neuroprotectant FK506, whose role in epilepsy was poorly understood. Dr. Liu believed the interaction may provide a critical link between TSC-Rheb and the mTOR signaling pathway that might provide a novel therapeutic application of FK506 and its derivatives in TSC-associated neurological disorders. Results from this study showed that Rheb activates mTOR by preventing the association of FKBP38 with mTOR. FKBP38 is an inherent direct inhibitor of mTOR, and Rheb activates mTOR by preventing its association with FKBP38. Additionally, as the known neuroprotectant FK506 specifically interacts with FKBP38, these studies introduced a new idea for the application of FK506 and its derivative in the treatment of TSC-associated neurological disorders such as epilepsy.

Dr. Akira Yoshii (FY08; Massachusetts Institute of Technology/University of Illinois, Chicago) is testing the hypothesis that the balance between excitation and inhibition is skewed in TSC and that this synaptic dysregulation is caused by altered protein synthesis. At the time, it was unknown which neuronal proteins mTOR regulates and how malfunctions in the TSC/mTOR pathway result in the neuronal defects and neurological symptoms observed in TSC. Studies in Tsc1-deleted neurons showed that up and down regulations of synaptic proteins are associated with autism and epilepsy. Abnormal balance between excitation and inhibition was also found in TSC-1 deleted neurons. This synaptic dysregulation may provide a new therapeutic target for future treatment for neurological symptoms in TSC such as epilepsy, mental retardation, and autistic behaviors.

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