The role of NPRL2 loss in focal cortical dysplasia

Project Summary Malformations of brain development are a common cause of neurological disorders in children. The most common of these neurodevelopmental disorders is the large group of malformations of cortical development (MCD) characterized by disruption of the structure of the cerebral cortex (e.g., enhanced cell size, altered lamination). Somatic mutations have been identified in regulatory genes of the PI3K-AKT3-mTOR (mTOR) pathway in the brain tissue of patients with these MCD collectively termed ‘mTORopathies.’ Focal cortical dysplasia is a particularly challenging mTORopathy due to the presence of highly epileptogenic lesions within the cortex that are often resistant to medication and/or difficult to resect. The most common genetic variants causing FCD are found in genes that encode protein subunits forming the GATOR1 complex: DEPDC5, NPRL2, and NPRL3- a negative regulator of mTOR signaling. Many studies have linked variants in DEPDC5 and NPRL3 to mTOR pathway hyperactivation, MCD, and seizures, but there few studies functionally validating or modeling variants in NPRL2 and, currently, mTOR inhibitors are not used to treat epilepsy in these patients. This project seeks to investigate the effects of Nprl2 loss in vitro and in vivo and to identify the mTOR-dependent transcriptomic changes that occur as a result of Nprl2 KO. The results of this proposal stand to provide a deep functional and transcriptomic understanding of NPRL2 variant associated phenotypes, provide pre-clinical support for the use of mTOR inhibitors in effected individuals, and identify novel therapeutic targets downstream of mTOR that may provide precision therapy options in the future.