Unit:
Τομέας Βασικών ΕπιστημώνLibrary of the School of Health Sciences
Dissertation committee:
Στεφανής Λεωνίδας, καθηγητής , τμήμα Ιατρικής, ΕΚΠΑ
Βεκρέλλης Κωνσταντίνος, ερευνητής Β' ΄, ΙΙΒΕΕΑ
Πολίτης Παναγιώτης, ερευνητής Γ' ΄, ΙΙΒΕΕΑ
Ταραβήρας Σταύρος, καθηγητής, τμήμα Ιατρικής, Πανεπιστήμιο Πατρών
Ευθυμιόπουλος Σπύρος, Αναπληρωτής καθηγητής, τμήμα Βιολογίας, ΕΚΠΑ
Παπαζαφείρη Παναγιώτα, Αναπληρώτρια καθηγήτρια, τμήμα Βιολογίας, ΕΚΠΑ
Δάλλα Χρίστινα, Επίκουρος καθηγήτρια, τμήμα Ιατρικής, ΕΚΠΑ
Original Title:
The role of Chaperone Mediated Autophagy in the Central Nervous System
Translated title:
The role of Chaperone Mediated Autophagy in the Central Nervous System
Summary:
Protein degradation systems have profound effects on signaling pathways and molecular networks that regulate organogenesis. Although autophagy-mediated protein degradation has been strongly associated with brain function and related diseases, its involvement in neural development remains unclear. Chaperone Mediated Autophagy (CMA), one of the main lysosomal degradation systems, has been linked to neurodegenerative diseases and neurodevelopmental disorders, however, nothing is known about its physiological role in mammalian brain development. Here we identify a novel regulatory role of CMA pathway in Neural Stem Cell (NSC) differentiation during development. In particular, we show that CMA is highly active in NSCs and that LAMP2A, the principal limiting component of CMA, together with HSC70 (HSPA8), another component of CMA, are strongly expressed in ex vivo cultured NSCs and embryonic rodent brain. Interestingly, LAMP2A expression pattern is associated with induction of neurogenesis. Most importantly, overexpression and loss of function experiments in NSCs, suggest an inductive role of CMA in neuronal differentiation. Mechanistically, we provide evidence that LAMP2A is involved in NSC fate decisions by interfering with Notch1 signaling pathway. Forced expression of LAMP2A reduces the protein levels of Notch1 Intracellular Domain (NICD) as well as expression of downstream effector genes, Hes1 and Hes5. Consistently, a CMA recognition motif (KFERQ-like) on the NICD peptide sequence was identified with functional importance in the ability of NICD to activate downstream genes and CMA-mediated degradation. Collectively, our data suggest a key role for LAMP2A and CMA in the regulation of neuronal fate acquisition via direct targeting of NICD activity.
Main subject category:
Health Sciences
Number of references:
141
