# Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment

## TL;DR

This study shows that inhibiting MDM2 can restore spastin levels and functions, offering a potential treatment for Hereditary Spastic Paraplegia.

## Contribution

MDM2 is identified as a novel interactor of spastin and a potential druggable regulator of its protein levels.

## Key findings

- MDM2 interacts with spastin's MIT domain and regulates its levels post-transcriptionally.
- Nutlin-3a, an MDM2 inhibitor, restores spastin levels and functions in deficient cells.
- Spastin functions like cytokinetic abscission and transferrin receptor sorting are recovered with MDM2 inhibition.

## Abstract

Spastin is a microtubule (MT) severing enzyme that regulates several cell functions associated with MT dynamics. A reduction in spastin protein levels is responsible for approximately 40% of cases of Hereditary Spastic Paraplegia (HSP), a neurodegenerative disease. Currently, there is no cure for HSP but strategies to induce a recovery of spastin levels are emerging as potential therapeutic approaches. Here, we show that MDM2 interacts with spastin MT-interacting and trafficking (MIT) domain. By biochemical and functional experiments, we demonstrate that MDM2 binds spastin and regulates its levels in a post-transcriptional manner independently of the E3 ubiquitin ligase activity. Of relevance, treatment of spastin-deficient cells with the MDM2 inhibitor Nutlin-3a can restore spastin levels and functions, such as cytokinetic abscission and sorting of transferrin receptor. These findings identify MDM2 as a novel interactor of spastin and a potential druggable regulator of its protein levels.