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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,3]]},"abstract":"<jats:p>\n                    The molecular circadian clock is a ubiquitous transcriptional\u2013translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-\u03b1 (\n                    <jats:italic toggle=\"yes\">Nr1d1<\/jats:italic>\n                    ) and REV-ERB-\u03b2 (\n                    <jats:italic toggle=\"yes\">Nr1d2<\/jats:italic>\n                    ) are components of the core circadian clock which regulate metabolism, neuroinflammatory responses, synaptic pruning, and protein aggregation, though the cell type\u2013specific effects and relative compensatory effects of REV-ERB-\u03b1 AND -\u03b2 in the brain are unknown. To study the CNS functions of REV-ERBs, we developed mouse lines with global or astrocyte-specific, conditional knockout of both REV-ERB-\u03b1 and -\u03b2. We demonstrate that inducible postnatal global deletion of both REV-ERB-\u03b1 and -\u03b2 unmasks extensive transcriptional changes in the brain in disease-relevant pathways such as protein catabolism, complement, and oxidative stress which are not observed with REV-ERB-\u03b1 deletion alone, and drives spontaneous astrocyte reactivity. Astrocyte-specific deletion of REV-ERB-\u03b1\/-\u03b2 recapitulates this spontaneous astrocyte reactivity phenotype, indicating that REV-ERBs regulate astrocyte activation in a cell-autonomous manner downstream of the core circadian clock. Upstream transcription factor analysis revealed that REV-ERB-\u03b1\/-\u03b2 repress transcription of\n                    <jats:italic toggle=\"yes\">Stat3<\/jats:italic>\n                    , and astrocytic deletion of REV-ERBs induced astrocytic STAT3 expression and downstream STAT3-mediated gene expression, providing a mechanistic link to the astrocyte reactivity shift. Dual REV-ERB deletion enhanced astrocyte alpha-synuclein uptake and protein degradation in vitro and mitigated alpha-synuclein spreading pathology in an in vivo model of Parkinson\u2019s Disease. This study reveals REV-ERBs as regulators of astrocyte function and implicates astrocyte REV-ERBs as potential therapeutic targets to prevent synucleinopathies and other neurodegenerative pathologies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2511093123","type":"journal-article","created":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T17:06:26Z","timestamp":1769792786000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["REV-ERB-alpha and -beta coordinately regulate astrocyte reactivity and proteostatic function"],"prefix":"10.1073","volume":"123","author":[{"given":"Collin J.","family":"Nadarajah","sequence":"first","affiliation":[{"name":"Department of Neurology, Washington University School of Medicine","place":["St. Louis"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0924-9947","authenticated-orcid":false,"given":"Michelle 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