Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases
Abstract NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S pro...
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Nature Portfolio
2025-01-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-84479-w |
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| author | Fikret Sahin Aslihan Gunel Buse Turegun Atasoy Ulku Guler Bekir Salih Isinsu Kuzu Mehmet Taspinar Ozgur Cinar Selda Kahveci |
| author_facet | Fikret Sahin Aslihan Gunel Buse Turegun Atasoy Ulku Guler Bekir Salih Isinsu Kuzu Mehmet Taspinar Ozgur Cinar Selda Kahveci |
| author_sort | Fikret Sahin |
| collection | DOAJ |
| description | Abstract NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimer’s and Parkinson’s. In our mouse model experiment, ketamine administration notably altered brain synaptic protein profiles within two hours, significantly downregulating proteins strongly associated with Alzheimer’s and Parkinson’s diseases. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling—a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, which is crucial as proteasome activity declines with age, leading to protein aggregation and disease symptoms. Therefore, these findings hold promise for new treatment options not only for brain diseases but also for other systemic conditions associated with unfolded or misfolded proteins. |
| format | Article |
| id | doaj-art-b44ec56ad85b4b808166637ffcf6df7e |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-b44ec56ad85b4b808166637ffcf6df7e2025-01-19T12:22:37ZengNature PortfolioScientific Reports2045-23222025-01-0115112710.1038/s41598-024-84479-wEnhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseasesFikret Sahin0Aslihan Gunel1Buse Turegun Atasoy2Ulku Guler3Bekir Salih4Isinsu Kuzu5Mehmet Taspinar6Ozgur Cinar7Selda Kahveci8Department of Medical Microbiology, Ankara University School of MedicineFaculty of Arts and Science Department of Chemistry-Biochemistry, Kırşehir Ahi Evran UniversityDepartment of Medical Microbiology, Ankara University School of MedicineDepartment of Chemistry, Hacettepe UniversityDepartment of Chemistry, Hacettepe UniversityDepartment of Medical Pathology, Ankara University School of MedicineDepartment of Medical Biology, Aksaray University School of MedicineDepartment of Histology and Embryology, Ankara University School of MedicineDepartment of Histology and Embryology, Ankara University School of MedicineAbstract NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases and major depression. The mechanism by which these drugs correct the aforementioned diseases is still unknown. Our study reveals that these antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal in neurodegenerative diseases like Alzheimer’s and Parkinson’s. In our mouse model experiment, ketamine administration notably altered brain synaptic protein profiles within two hours, significantly downregulating proteins strongly associated with Alzheimer’s and Parkinson’s diseases. Furthermore, the altered proteins exhibited enrichment in terms related to plasticity and potentiation, including retrograde endocannabinoid signaling—a pivotal pathway in both short- and long-term plasticity that may elucidate the long-lasting effects of ketamine in major depression. Via the ubiquitin-independent 20S proteasome pathway (UIPS), these drugs maintain cellular protein homeostasis, which is crucial as proteasome activity declines with age, leading to protein aggregation and disease symptoms. Therefore, these findings hold promise for new treatment options not only for brain diseases but also for other systemic conditions associated with unfolded or misfolded proteins.https://doi.org/10.1038/s41598-024-84479-wN-methyl-D-aspartate receptor (NMDAR) antagonistsProteasomeNeurodegenerative diseasesMental diseases |
| spellingShingle | Fikret Sahin Aslihan Gunel Buse Turegun Atasoy Ulku Guler Bekir Salih Isinsu Kuzu Mehmet Taspinar Ozgur Cinar Selda Kahveci Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases Scientific Reports N-methyl-D-aspartate receptor (NMDAR) antagonists Proteasome Neurodegenerative diseases Mental diseases |
| title | Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases |
| title_full | Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases |
| title_fullStr | Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases |
| title_full_unstemmed | Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases |
| title_short | Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases |
| title_sort | enhancing proteasome activity by nmdar antagonists explains their therapeutic effect in neurodegenerative and mental diseases |
| topic | N-methyl-D-aspartate receptor (NMDAR) antagonists Proteasome Neurodegenerative diseases Mental diseases |
| url | https://doi.org/10.1038/s41598-024-84479-w |
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