LAMP2A-dependent chaperone mediated autophagy regulates Notch signaling and controls neural stem cell differentiation.

Protein degradation systems have profound effects on signaling pathways and molecular networks that regulate organogenesis. Chaperone Mediated Autophagy (CMA) has been linked to neurodegenerative and neurodevelopmental diseases, however, its role in mammalian brain development remains poorly understood. Here, we identify a regulatory role of CMA pathway in neural stem cell (NSC) differentiation. We show that CMA is active in NSCs, while expression of LAMP2A, the principal limiting component of CMA, is associated with the induction of neurogenesis. Most importantly, overexpression and loss-of-function experiments of LAMP2A in NSCs suggest an inductive role of CMA in neuronal differentiation. Moreover, we demonstrate that LAMP2A is involved in NSC fate decisions by interfering with NOTCH1 signaling pathway. Our data support a model in which LAMP2A-dependent CMA contributes to neuronal fate acquisition through suppression of NOTCH1 signaling, and provide a mechanistic framework that may help explain the reported genetic involvement of LAMP2 gene and CMA in neurodevelopmental disorders.