biostudies-literaturePool EHGerman Research FoundationEagles Autism FoundationSimons Foundation Autism Research InitiativeNIDDK NIH HHSNIA NIH HHSUniversity of California, San DiegoNCI NIH HHSNINDS NIH HHSNational Institutes of HealthFibrolamellar Cancer FoundationUS Department of DefenseNIGMS NIH HHS115797https://www.ebi.ac.uk/biostudies/studies/S-EPMC12369641biostudies-literatureUnknown44(6)Spatiotemporal regulation of key-node signaling molecules, such as 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), is critical for normal cell physiology and susceptible to dysregulation in disease. Liquid-liquid phase separation (LLPS) is broadly recognized as a fundamental component of signal regulation, yet the connections between physiological and disease-linked biomolecular condensates are not well understood. Here, we show that an understudied, brain-specific PKA regulatory subunit, RIβ, forms biomolecular condensates with distinct features from the ubiquitous isoform, RIα. We demonstrate that two RIβ mutants linked to neurodegenerative (L50R) or neurodevelopmental (R335W) pathologies produce aberrant condensates that trap the PKA catalytic subunit within Cell reportsAberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits.PMC12369641R01 DK073368T32 NS045549R21 AG080472R35 CA197622R35 GM130389T32 GM008326GRK 2749 #448909517T32 GM067795R21 AG080472-02AR230307Pane VZhang JLee HNHardy JCTaylor SSMehta SStrack SHerberg FWPool EHGlebov-McCloud AfalseAberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits.Spatiotemporal regulation of key-node signaling molecules, such as 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), is critical for normal cell physiology and susceptible to dysregulation in disease. Liquid-liquid phase separation (LLPS) is broadly recognized as a fundamental component of signal regulation, yet the connections between physiological and disease-linked biomolecular condensates are not well understood. Here, we show that an understudied, brain-specific PKA regulatory subunit, RIβ, forms biomolecular condensates with distinct features from the ubiquitous isoform, RIα. We demonstrate that two RIβ mutants linked to neurodegenerative (L50R) or neurodevelopmental (R335W) pathologies produce aberrant condensates that trap the PKA catalytic subunit within 2025-01-01T00:00:00Z2025 Jun2026-07-15T14:18:46.754Z2026-07-09T10:15:25.102ZS-EPMC123696414051262510.1016/j.celrep.2025.115797