UCHL1-Mediated Spastin Degradation Regulates Microtubule Severing and Hippocampal Neurite Outgrowth

As a key component of the cytoskeleton, microtubule dynamic provides structural support for neurite outgrowth. Spastin, a microtubule severing enzyme associated with hereditary spastic paraplegia (HSP), is crucial for the growth and branching of neuronal processes. Thus, the activity and function of spastin need to be strictly regulated. However, the mechanism by which spastin protein levels are regulated is still poorly understood. In the current study, we showed that UCHL1 interacted with spastin via mass spectrometry, GST-pulldown and immunoprecipitation assays. Overexpression of UCHL1 decreased the protein level of spastin, while the genetic knockdown of UCHL1 increased that of spastin. CHX chase assay showed that UCHL1 regulated the protein degradation of spastin. Application of proteasome inhibitor MG-132 suppressed UCHL1-mediated spastin degradation. Furthermore, overexpression or knockout of UCHL1 can inhibit or restore spastin-mediated microtubule severing, thereby regulating neuronal length and branch formation. These findings reveal the important regulatory mechanism of UCHL1 on spastin-mediated neurite outgrowth.