Work

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

Year: 2022

Type: preprint

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.

Source: Research Square

DOI: 10.21203/rs.3.rs-2320747/v1