Journal article
Aberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits
Cell reports (Cambridge), Vol.44(6), 115797
06/11/2025
DOI: 10.1016/j.celrep.2025.115797
PMCID: PMC12369641
PMID: 40512625
Abstract
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 a gel-like matrix or cAMP-insensitive holoenzyme complex, respectively. RIβ
condensates, in particular, lead to disrupted spatiotemporal control of PKA signaling and diminished PKA activity, resulting in phenotypic hallmarks of neurodegeneration. Our work highlights the functional importance of biomolecular condensates and the critical link between dysregulated LLPS and neurological disorders.
Details
- Title: Subtitle
- Aberrant phase separation of two PKA RIβ neurological disorder mutants leads to mechanistically distinct signaling deficits
- Creators
- Emily H Pool - University of California San DiegoAlexander Glebov-McCloud - Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USAHa Neul Lee - University of California San DiegoJulia C Hardy - University of California San DiegoValeria Pane - University of KasselFriedrich W Herberg - University of KasselSusan S Taylor - University of California San DiegoSohum Mehta - University of California San DiegoStefan Strack - Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, University of Iowa, Iowa City, IA 52242, USA. Electronic address: stefan-strack@uiowa.eduJin Zhang - University of California San Diego
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.44(6), 115797
- DOI
- 10.1016/j.celrep.2025.115797
- PMID
- 40512625
- PMCID
- PMC12369641
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Publisher
- CELL PRESS
- Grant note
- NIH: R35 CA197622, R01 DK073368, R35 GM130389, R21 AG080472-02, T32 GM008326, T32 GM067795, T32 NS045549 Fibrolamellar Cancer FoundationEagles Autism FoundationSimons Foundation Autism Research InitiativeDepartment of Defense: AR230307 Jordan's Guardian Angels: A19-2853-S004 DFG-funded Research Training Group "multiscale clocks": GRK 2749, 448909517
We thank J. Silvio Gutkind for CRE constructs, Yuliang Ma and Jessica Bruystens for insights into RI (3 behavior, and Sabrina Dorfler and Yufang Kong for molecular biology support. We also thank Eric Griffis and Peng Guo of the UCSD Nikon Imaging Center, Sara Parker from Nikon Imaging, and Cody Fine at the UCSD Human Embryonic Stem Cell Core for assistance with microscopy and flow cytometry, respectively. We thank members of the Jin Zhang and Stefan Strack labs for their support. This work was supported by NIH grants R35 CA197622 and R01 DK073368 (to J.Z.) , R35 GM130389 (to S.S. T.) , R21 AG080472-02 (to S.S. and S.S.T.) , a Fibrolamellar Cancer Foundation grant (to J.Z.) , grants from the Eagles Autism Foundation, the Simons Foundation Autism Research Initiative, the Department of Defense (AR230307) , and Jordan's Guardian Angels (A19-2853-S004) (to S.S.) , and the DFG-funded Research Training Group "multiscale clocks" (GRK 2749 #448909517) (to F. W.H.) . E.H.P. acknowledges support from NIH T32 GM008326. A.G.-M. acknowledges support from NIH T32 GM067795 and T32 NS045549.
- Language
- English
- Date published
- 06/11/2025
- Academic Unit
- Pathology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9984829887902771
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