Event Details:
Stanford Neurosciences Institute Molecular Neuroscience Junior Faculty Candidate
Abstract: Childhood neurodegenerative disorders are heterogeneous and individually rare conditions. Yet, collectively they represent one of the most common clinical problems in pediatric neurology given that a large proportion of them are of unknown cause and treatment options are mostly non-existent. In order to uncover novel disease mechanisms we focused on children with inherited cerebellar degeneration and ataxia. Exome sequencing on a cohort of 111 consanguineous families revealed several novel causative genes, AMPD2 and SNX14 being the most recurrently mutated ones. We found that mutations in SNX14 lead to lysosome-autophagosome dysfunction, for which cerebellar cells are more sensitive. Mutations in AMPD2 lead to a reduction of energy for protein synthesis and a potentially preventable loss of brainstem and cerebellar structures. Being widely expressed, both AMPD2 and SNX14 inactivation mostly perturb specific neuronal populations. Moreover, both have an impact on protein homeostasis. Thus, it is our goal to better understand how protein homeostasis regulation may determine selective neuronal vulnerability. Indeed, specific neuronal vulnerability to ubiquitous stimuli is common in many neurological diseases. This emphasizes the need to better characterize particular features that distinguish each neuronal population in health and disease conditions, which will ultimately lead to uncover specific therapeutic targets.