PTEN Negatively Regulates Spastin Ser210 Phosphorylation To Modulate GluA1 Surface Trafficking and Excitatory Synaptic Transmission.

Abstract

As a key component of the cytoskeleton, microtubule dynamics provide structural support for neurite growth. Spastin plays a critical role in reshaping microtubule arrangement, which is essential for axon development and regeneration. However, the mechanism by which spastin is activated and functions remains unclear. In this study, we discovered that phosphorylation of spastin at Ser210 promotes dendrite growth and surface expression of GluA1 in neurons, enhancing synaptic transmission. Conversely, dephosphorylation of spastin inhibits dendrite growth and surface expression of GluA1, weakening synaptic transmission. PTEN interacts with the MIT domain of spastin through its C-terminal region, resulting in reduced spastin phosphorylation expression levels. This process suppresses the transport of the AMPA receptor GluA1 subunit, thereby modulating neurite outgrowth and weakening synaptic transmission. In conclusion, our research indicates that PTEN is the pathway that regulates the phosphorylation of spastin, providing an important reference for the treatment of neurological diseases characterized by microtubule dysregulation.