Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases

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dc.contributor.authorŞahin, Fikret
dc.contributor.authorGünel, Aslıhan
dc.contributor.authorAtasoy, Buse Türegün
dc.contributor.authorGüler, Ülkü
dc.contributor.authorSalih, Bekir
dc.contributor.authorKuzu, Işınsu
dc.contributor.authorTaşpınar, Mehmet
dc.contributor.authorÇınar, Özgür
dc.contributor.authorKahveci, Selda
dc.date.accessioned2025-04-22T06:24:14Z
dc.date.available2025-04-22T06:24:14Z
dc.date.issued2025
dc.departmentTıp Fakültesi
dc.description.abstractNMDAR 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.
dc.identifier.doi10.1038/s41598-024-84479-w
dc.identifier.issue1
dc.identifier.scopus2-s2.0-85215578041
dc.identifier.scopusqualityQ1
dc.identifier.urihttps://dx.doi.org/10.1038/s41598-024-84479-w
dc.identifier.urihttps://hdl.handle.net/20.500.12451/13090
dc.identifier.volume15
dc.identifier.wos001397260500034
dc.identifier.wosqualityQ1
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.indekslendigikaynakWeb of Science
dc.institutionauthorTaşpınar, Mehmet
dc.language.isoen
dc.publisherNature Research
dc.relation.ispartofScientific Reports
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectMental Diseases
dc.subjectN-methyl-D-aspartate Receptor (NMDAR) Antagonists
dc.subjectNeurodegenerative Diseases
dc.subjectProteasome
dc.titleEnhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases
dc.typeArticle

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