The Manton Center for Orphan Disease Research
Mustafa Sahin, MD, PhD
Role of RNA Regulatory Networks in Tuberous Sclerosis
Tuberous sclerosis complex (TSC) is a rare genetic disease that causes epilepsy, mental retardation, autism and benign tumors throughout the body. One of the major cellular functions of the TSC1/TSC2 complex is to limit protein synthesis and regulate cell size by inhibiting the mammalian target of rapamycin (mTOR) pathway. Using mouse models and neuronal cultures, we have shown that the Tsc1 and Tsc2 genes play crucial roles in axon specification, guidance and myelination (Choi et al, Genes Dev 08; Nie et al., Nat Neurosci 10; Meikle et al., J Neurosci 08). Furthermore, we have demonstrated that TSC patients have abnormalities in white matter connectivity similar to that we detect in Tsc-deficient mouse models (Krishnan et al., Pediatr Neurol 10). While we have made significant progress in understanding the role of TSC/mTOR pathway in neurons, the molecular mechanisms by which TSC/mTOR regulate neuronal structure and function still remain largely unclear. We have recently started to investigate the relationship between the TSC/mTOR pathway and another cellular mechanism that regulates protein synthesis: miRNAs. Their role at synapses, ability to modulate large number of genes and modify pathogenesis of single gene defects all raise the intriguing possibility that miRNAs may play a role in the pathogenesis of neurodevelopmental disorders. In our preliminary data, we started to examine miRNA profiles in Tsc-deficient neurons and found that the expression of two microRNAs increased when Tsc2 is knocked down. Here we propose to investigate further the role of miRNAs in TSC. We have two specific aims: 1. To identify and characterize microRNAs regulated by TSC/mTOR pathway in rodent neurons, and 2. To test whether the changes in the expression of miRNAs are found in TSC patient peripheral blood samples. Beyond, providing insight into the pathophysiology of tuberous sclerosis, our experiments may also have implications for other diseases in which mTOR pathway is hyperactive such as FXS, PTEN hamartoma syndrome, and neurofibromatosis as well as non-syndromic neurodevelopmental disorders.