UCHL1 inhibited by A1 astrocytes facilitates aggregates clearance to promote neural stem cells activation after spinal cord injury

Abstract

AbstractSpinal cord injury (SCI) is a devastating central nervous system (CNS) disease with no satisfying therapies available. Mobilizing endogenous neural stem cells (NSCs) to trigger intrinsic regeneration exhibits promising potentials for SCI repair. However, neurogenesis from endogenous NSCs is extremely restricted in the non-neurogenic spinal cord after SCI. Accumulation of protein aggregates has been shown to impede quiescent NSCs activation and the subsequent neurogenesis. Here, we found that ubiquitin c-terminal hydrolase l-1 (UCHL1), a deubiquitinating enzyme, functioned to regulate NSCs activation and neurogenesis by reducing protein aggregations through ubiquitin-proteasome pathway (UPP) in vitro. Upregulation of UCHL1 in spinal cord NSCs of rats with complete transection SCI efficiently enhanced NSCs proliferation and neurogenesis, leading to significantly improved functional outcomes. Based on protein microarray analysis of cerebrospinal fluid (CSF), our results revealed that A1 reactive astrocytes acted to restrict NSCs neurogenesis by negatively regulating UCHL1-depentdent protein aggregates removal via the C3/Nrf2 signaling. Indeed, blockade of A1 astrocytes using neutralizing antibodies after SCI also led to NSCs activation, increased neurogenesis and remarkably enhanced motor function recovery. This study not only revealed a novel mechanism regulating NSCs-medicated neurogenesis in the spinal cord, but also provided new molecular targets for neural repair strategies after SCI.Graphical AbstractHighlightsUCHL1 facilitates NSCs activation by clearing intracellular protein aggregates through ubiquitin-proteasome approachA1 reactive astrocytes result in down-regulation of UCHL1 to inhibit spinal NSCs activation by C3 after SCIOverexpression of UCHL1 or blockade of A1 astrocytes lead to NSCs activation and neurons formation to promote SCI repair via UCHL1-proteasome pathway