{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Nadarajah CJ"],"funding":["NIDDK NIH HHS","NIA NIH HHS","HHS | NIH | National Institute on Aging (NIA)","HHS | NIH | NIDDK | Division of Diabetes, Endocrinology, and Metabolic Diseases (DEM)"],"pagination":["e2511093123"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12867698"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["123(5)"],"pubmed_abstract":["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."],"journal":["Proceedings of the National Academy of Sciences of the United States of America"],"pubmed_title":["REV-ERB-alpha and -beta coordinately regulate astrocyte reactivity and proteostatic function."],"pmcid":["PMC12867698"],"funding_grant_id":["R01 DK045586","R01AG05451707","R01DK45586","R21 AG089851","R21AG089851","R01AG06374304"],"pubmed_authors":["Nadarajah CJ","Lee J","Sheehan PW","King MW","Lazar MA","Li MY","Musiek ES","Zhao G","Boyer K","Davis AA","Chen Y","Saliu IO","Dimitry JM","Quillin EI"],"additional_accession":[]},"is_claimable":false,"name":"REV-ERB-alpha and -beta coordinately regulate astrocyte reactivity and proteostatic function.","description":"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.","dates":{"release":"2026-01-01T00:00:00Z","publication":"2026 Feb","modification":"2026-07-05T03:17:13.938Z","creation":"2026-07-05T03:12:24.259Z"},"accession":"S-EPMC12867698","cross_references":{"pubmed":["41615759"],"doi":["10.1073/pnas.2511093123"]}}