Molecular mechanisms of a neurodevelopmental seizure disorder

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Project Summary Disrupting neurodevelopmental processes leads to a range of neurological, psychiatric and behavioral disorders. In the US, one in six children exhibit some form of neurodevelopmental disorder, ranging from severe dysfunction to mild social-behavioral difficulties. Genetics plays a critical role and many genes have been implicated as risk factors for diverse neurodevelopmental disorders. However, common themes that are shared by multiple neurodevelopmental disorders include disturbances to the autophagy-lysosome pathway and the dysregulation of mTORC1 kinase signaling. A common co-morbidity of neurodevelopmental disorders with mutations affecting the autophagy-lysosome pathway and mTORC1 dysregulation are seizures, implying that these fundamental cellular processes also underlie an imbalance in excitatory and inhibitory activities. The goal of this project is to uncover a new molecular connection between the autophagy-lysosome pathway and mTORC1 dysregulation that leads to neurodevelopmental disorders and epilepsy. In yeast we found that the yeast Kctd (Whi2 protein/Whi2p) is a potent negative regulator of TORC1 and is required for induction of autophagy in low nutrient conditions. Based on findings from yeast models, we identified mammalian counterparts as a family of understudied human genes known as the potassium channel tetramerization domain proteins (KCTDs). The long-established binding partners of yeast Kctd (Whi2) are the yeast protein phosphatases Psr1 and Psr2, which have obvious human homologs, the CTDSP/CSP phosphatase family. We will test the hypothesis that KCTD family proteins are regulators of a protein quality control pathway that is also connected to the mTORC1 signaling pathway. Several KCTD family members have been linked to neurodevelopmental disorders including epilepsies, autism and schizophrenia. We propose to translate our unique insights gained from studies in yeast to delineate an important molecular mechanism of pathogenesis in the brain using cellular and biochemical approaches and a mouse model that recapitulates important aspects human disease.