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bioRxiv · 10.1101/2021.09.23.461600

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

Ding, L.·Chu, W.·Xia, Y.·Li, T.·Shi, M.·Zhou, F.-Q.·Deng, Y.
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Abstract

Activation of endogenous neural stem cells (NSCs) is critically important for the adult neurogenesis. However, NSC activation is extremely limited after spinal cord injury (SCI). Recent evidence suggests that accumulation of protein aggregates impedes quiescent NSC activation. Here, we found ubiquitin c-terminal hydrolase l-1 (UCHL1), an important deubiquitinating enzyme, functioned to facilitate NSC activation by clearing protein aggregations through ubiquitin-proteasome approach. Upregulation of UCHL1 enhanced NSC proliferation in the spinal cord after injury. Based on protein microarray analysis of SCI cerebrospinal fluid, it is further revealed that C3+ neurotoxic reactive astrocytes negatively regulated UCHL1 and aggresome clearance through C3/C3aR signaling, resulting in reduced capacity of NSC to activate. Furthermore, blockade of reactive astrocytes or C3/C3aR pathway led to enhanced NSC activation post-SCI. Together, this study elucidated a mechanism regulating NSC activation in the adult spinal cord involving the UCHL1-proteasome approach, which may provide potential molecular targets for NSC fate regulation.

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Ding, L., Chu, W., Xia, Y., Li, T., Shi, M., Zhou, F.-Q., Deng, Y.. 2021-09-24. UCHL1 inhibited by A1 astrocytes facilitates aggregates clearance to promote neural stem cells activation after spinal cord injury. https://doi.org/10.1101/2021.09.23.461600

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