biostudies-literatureNadarajah CJNIDDK NIH HHSNIA NIH HHSHHS | NIH | National Institute on Aging (NIA)HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)e2511093123https://www.ebi.ac.uk/biostudies/studies/S-EPMC12867698biostudies-literatureUnknown123(5)The molecular circadian clock is a ubiquitous transcriptional-translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-α (<i>Nr1d1</i>) and REV-ERB-β (<i>Nr1d2</i>) are components of the core circadian clock which regulate metabolism, neuroinflammatory responses, synaptic pruning, and protein aggregation, though the cell type-specific effects and relative compensatory effects of REV-ERB-α AND -β 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-α and -β. We demonstrate that inducible postnatal global deletion of both REV-ERB-α and -β 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-α deletion alone, and drives spontaneous astrocyte reactivity. Astrocyte-specific deletion of REV-ERB-α/-β 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-α/-β repress transcription of <i>Stat3</i>, 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's 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.Proceedings of the National Academy of Sciences of the United States of AmericaREV-ERB-alpha and -beta coordinately regulate astrocyte reactivity and proteostatic function.PMC12867698R01 DK045586R01AG05451707R01DK45586R21 AG089851R21AG089851R01AG06374304Nadarajah CJLee JSheehan PWKing MWLazar MALi MYMusiek ESZhao GBoyer KDavis AAChen YSaliu IODimitry JMQuillin EIfalseREV-ERB-alpha and -beta coordinately regulate astrocyte reactivity and proteostatic function.The molecular circadian clock is a ubiquitous transcriptional-translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-α (<i>Nr1d1</i>) and REV-ERB-β (<i>Nr1d2</i>) are components of the core circadian clock which regulate metabolism, neuroinflammatory responses, synaptic pruning, and protein aggregation, though the cell type-specific effects and relative compensatory effects of REV-ERB-α AND -β 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-α and -β. We demonstrate that inducible postnatal global deletion of both REV-ERB-α and -β 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-α deletion alone, and drives spontaneous astrocyte reactivity. Astrocyte-specific deletion of REV-ERB-α/-β 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-α/-β repress transcription of <i>Stat3</i>, 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's 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.2026-01-01T00:00:00Z2026 Feb2026-07-05T03:17:13.938Z2026-07-05T03:12:24.259ZS-EPMC128676984161575910.1073/pnas.2511093123