Boosting Proteasome Activity: A Novel Mechanism of NMDAR Blockers Against Neurodegeneration

Boosting Proteasome Activity: A Novel Mechanism of NMDAR Blockers Against Neurodegeneration | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Boosting Proteasome Activity: A Novel Mechanism of NMDAR Blockers Against Neurodegeneration Fikret Sahin, Aslihan Gunel, Buse Turegun Atasoy, Ulku Guler, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4973153/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 13 Jan, 2025 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version 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. Biological sciences/Cell biology Biological sciences/Chemical biology Biological sciences/Molecular biology Biological sciences/Neuroscience Health sciences/Diseases Health sciences/Medical research Health sciences/Molecular medicine Health sciences/Neurology N-methyl-D-aspartate receptor (NMDAR) antagonists Proteasome neurodegenerative diseases mental diseases Full Text Additional Declarations No competing interests reported. Figures S1 to S11 and Tables S1, S2 are not available with this version. Supplementary Files SupplementaryexcelTableS1.xlsx SupplementaryexcelTableS2.xlsx SupplementaryexcelTableS3.xlsx SupplementaryexcelTableS4.xlsx SupplementaryexcelTableS5.xlsx SupplementaryexcelTableS6.xlsx SupplementaryexcelTableS7.xlsx SupplementaryexcelTableS8.xlsx SupplementaryexcelTableS9.xlsx SupplementaryexcelTableS10.xlsx Cite Share Download PDF Status: Published Journal Publication published 13 Jan, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 05 Nov, 2024 Reviews received at journal 01 Nov, 2024 Reviews received at journal 18 Oct, 2024 Reviewers agreed at journal 16 Oct, 2024 Reviewers agreed at journal 14 Oct, 2024 Reviewers agreed at journal 08 Sep, 2024 Reviewers invited by journal 06 Sep, 2024 Editor assigned by journal 06 Sep, 2024 Editor invited by journal 05 Sep, 2024 Submission checks completed at journal 03 Sep, 2024 First submitted to journal 25 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4973153","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":361022320,"identity":"a334bdb7-3df9-40b6-8838-bd13115786b4","order_by":0,"name":"Fikret 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