Regulation of neuronal survival by gamma protocadherins

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DESCRIPTION (provided by applicant): Neuronal death is not only essential in shaping the size and connectivity of the developing nervous system, but also contributes significantly to the pathogenesis of neurodegenerative diseases and stroke. Accumulating genetic evidence shows that clustered protocadherins (Pcdhs) play an important role in the regulation of neuronal survival. Our preliminary data show that PDCD10, also known as CCM3, a causative genetic defect for Cerebral Cavernous Malformations in human, acts downstream of Pcdh-?s to mediate this function. To better understand molecular pathways by which Pcdhs regulate neuronal survival, we will define the molecular pathways downstream of PDCD10 by evaluating the role of individual components in PDCD10 protein interaction network using genetically modified mouse models. PUBLIC HEALTH RELEVANCE: Developmental neuronal death ensures the appropriate size and connectivity of the nervous system and aberrant neuronal death in adulthood is commonly associated with chronic neurodegenerative diseases such as Alzheimer's disease, and acute cerebral ischaemia/stroke. The objective of this project is to elucidate how neurons signal through a large family of cell surface molecules-protocadherins to regulate neuronal survival during normal development and how misregulation of this pathway leads to neurodegeneration.