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

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.

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Publication Details

Journal
Cell Death Discovery
Published
2025-02-07
DOI
https://doi.org/10.1038/s41420-025-02333-y
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Cinzia Rinaldo, Giada Tisci, Silvia Soddu, Francesca Sardina et al.
Cell Death Discovery
Ubiquitin and proteasome pathways
article

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

Cinzia Rinaldo, Giada Tisci, Silvia Soddu, Francesca Sardina, Federica Polverino, Alessandro Paiardini, Elisabetta Falvo, Fabiola Moretti, Claudia Carsetti, Sonia Valentini
article en

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.

Cell Death DiscoveryVol. 11(1)
Institute of Molecular Biology and Pathology (IT), Expert System (Italy) (IT), National Research Council (IT), Institute of Cell Biology and Neurobiology (IT), Sapienza University of Rome (IT)
Fondazione Telethon, Ministero dell’Istruzione, dell’Università e della Ricerca, Consiglio Nazionale delle Ricerche, Fondazione Umberto Veronesi, AFM-Téléthon, Associazione Italiana per la Ricerca sul Cancro
Good health and well-being
Openalex Percentile: Top 98%
Ubiquitin and proteasome pathways
DOIOpen Access PDFOpenAlex
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