UCHL1 inhibited by reactive astrocytes facilitates aggregates clearance to promote neural stem cell activation

Abstract Activation of the endogenous neural stem cells (NSCs) is critically important for the adult neurogenesis. However, NSC activation is extremely limited in the non-neurogenic spinal cord after spinal cord injury (SCI). Recent evidence suggests that accumulation of protein aggregates impedes quiescent NSC activation. Here, we found that ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, functioned to facilitate NSC activation by clearing protein aggregations through ubiquitin-proteasome pathway. Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3+ neurotoxic reactive astrocytes negatively regulated UCHL1 and the subsequent protein aggregations clearance to restrict NSC activation via C3/C3aR signaling. Upregulation of UCHL1 and blockade of reactive astrocytes or C3/C3aR pathway efficiently enhanced Nestin+ NSC activation after SCI. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, providing a promising strategy and novel molecular targets for SCI repair.