{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:50:01Z","timestamp":1787010601361,"version":"build-2736575974"},"posted":{"date-parts":[[2025,3,2]]},"group-title":"Neuroscience","reference-count":84,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,2]],"date-time":"2025-03-02T00:00:00Z","timestamp":1740873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,2]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:p>\n                  The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15B\n                  <jats:sup>R658C<\/jats:sup>\n                  genetic variant associated with intellectual disability. By generating a novel mouse model that mimics this human condition, we revealed that this variant destabilizes the PPP1R15B\u2022PP1 phosphatase complex, resulting in chronic ISR activation, impaired protein synthesis, and deficits in long-term memory. Importantly, we found that the cognitive and synaptic deficits in\n                  <jats:italic>Ppp1r15b<\/jats:italic>\n                  <jats:sup>R658C<\/jats:sup>\n                  mice are directly due to ISR activation. Leveraging insights from evolutionary biology, we characterized DP71L, a viral orthologue of PPP1R15B, through detailed molecular and structural analyses, uncovering its mechanism of action as a potent pan-ISR inhibitor. Remarkably, we found that DP71L not only buffers cognitive decline associated with a wide array of conditions\u2014including Down syndrome, Alzheimer\u2019s disease and aging\u2014but also enhances long-term synaptic plasticity and memory in healthy mice. These findings highlight the promise of utilizing evolutionary insight to inform innovative therapeutic strategies.\n                <\/jats:p>","DOI":"10.1101\/2025.02.28.640897","type":"posted-content","created":{"date-parts":[[2025,3,2]],"date-time":"2025-03-02T14:15:16Z","timestamp":1740924916000},"source":"Crossref","is-referenced-by-count":2,"title":["Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction"],"prefix":"10.64898","author":[{"given":"Lucas C.","family":"Reineke","sequence":"first","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping Jun","family":"Zhu","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Udit","family":"Dalwadi","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean W.","family":"Dooling","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Liu","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I-Ching","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, Texas, 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Young-Baird","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Okoh","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santosh Kumar","family":"Kuncha","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akshara","family":"Kannan","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyekyung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, Texas, 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas A.","family":"Debeaubien","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan","family":"Croll","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. John","family":"Lee","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Arthur","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Dever","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Walter","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Chen","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Frost","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Costa-Mattioli","sequence":"additional","affiliation":[{"name":"Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA"},{"name":"Department of Neuroscience, Baylor College of Medicine, Houston, Texas, 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041111511727000_2025.02.28.640897v1.1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat5314"},{"key":"2026041111511727000_2025.02.28.640897v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00105-9"},{"key":"2026041111511727000_2025.02.28.640897v1.3","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.micro.59.031805.133833"},{"key":"2026041111511727000_2025.02.28.640897v1.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1400129111"},{"key":"2026041111511727000_2025.02.28.640897v1.5","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200308075"},{"key":"2026041111511727000_2025.02.28.640897v1.6","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.153.5.1011"},{"key":"2026041111511727000_2025.02.28.640897v1.7","unstructured":"7. 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