Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment
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 cu...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-02-01
|
| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02333-y |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823863264203767808 |
|---|---|
| author | Francesca Sardina Federica Polverino Sonia Valentini Claudia Carsetti Elisabetta Falvo Giada Tisci Silvia Soddu Fabiola Moretti Alessandro Paiardini Cinzia Rinaldo |
| author_facet | Francesca Sardina Federica Polverino Sonia Valentini Claudia Carsetti Elisabetta Falvo Giada Tisci Silvia Soddu Fabiola Moretti Alessandro Paiardini Cinzia Rinaldo |
| author_sort | Francesca Sardina |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-45e6b00493f648b8b09943a88e107c70 |
| institution | Kabale University |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-45e6b00493f648b8b09943a88e107c702025-02-09T12:12:30ZengNature Publishing GroupCell Death Discovery2058-77162025-02-011111910.1038/s41420-025-02333-yTargeting MDM2 affects spastin protein levels and functions: implications for HSP treatmentFrancesca Sardina0Federica Polverino1Sonia Valentini2Claudia Carsetti3Elisabetta Falvo4Giada Tisci5Silvia Soddu6Fabiola Moretti7Alessandro Paiardini8Cinzia Rinaldo9Institute of Molecular Biology and Pathology, Italian National Research Council, c/o Sapienza UniversityInstitute of Molecular Biology and Pathology, Italian National Research Council, c/o Sapienza UniversityInstitute of Biochemistry and Cell Biology, Italian National Research CouncilInstitute of Molecular Biology and Pathology, Italian National Research Council, c/o Sapienza UniversityInstitute of Molecular Biology and Pathology, Italian National Research Council, c/o Sapienza UniversityInstitute of Molecular Biology and Pathology, Italian National Research Council, c/o Sapienza UniversityUnit of Cellular Networks and Molecular Therapeutic Targets, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer InstituteInstitute of Biochemistry and Cell Biology, Italian National Research CouncilDepartment of Biochemical Sciences “A. Rossi Fanelli”, Sapienza UniversityInstitute of Molecular Biology and Pathology, Italian National Research Council, c/o Sapienza UniversityAbstract 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.https://doi.org/10.1038/s41420-025-02333-y |
| spellingShingle | Francesca Sardina Federica Polverino Sonia Valentini Claudia Carsetti Elisabetta Falvo Giada Tisci Silvia Soddu Fabiola Moretti Alessandro Paiardini Cinzia Rinaldo Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment Cell Death Discovery |
| title | Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment |
| title_full | Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment |
| title_fullStr | Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment |
| title_full_unstemmed | Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment |
| title_short | Targeting MDM2 affects spastin protein levels and functions: implications for HSP treatment |
| title_sort | targeting mdm2 affects spastin protein levels and functions implications for hsp treatment |
| url | https://doi.org/10.1038/s41420-025-02333-y |
| work_keys_str_mv | AT francescasardina targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment AT federicapolverino targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment AT soniavalentini targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment AT claudiacarsetti targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment AT elisabettafalvo targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment AT giadatisci targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment AT silviasoddu targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment AT fabiolamoretti targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment AT alessandropaiardini targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment AT cinziarinaldo targetingmdm2affectsspastinproteinlevelsandfunctionsimplicationsforhsptreatment |