229: Inhibiting PCBP2 condensates in Alzheimer’s

️ Episode 229: Inhibiting PCBP2 condensates in Alzheimer’s In this episode of PaperCast Base by Base, we explore Elevated PCBP2 forms liquid-like condensates that sequester mitochondrial and RNA-binding proteins, stabilize BACE1 mRNA, and promote amyloid pathology while the small molecule CN-0928 reduces PCBP2 via INTS1 to lower Aβ and improve cognition in AD models Study Highlights:PCBP2 protein is increased in AD patient brains and AD mouse models and forms enlarged, dynamic cytoplasmic condensates that undergo LLPS in vitro and in cells. PCBP2 condensates concentrate mitochondrial proteins and RNA-binding/NMD factors including UPF1, correlating with disrupted mitochondrial morphology, increased ROS, and reduced mitochondrial respiration. PCBP2 stabilizes BACE1 mRNA by sequestering NMD components into condensates and thereby impairs 3′UTR-dependent decay. The small molecule CN-0928 binds INTS1 at Arg-1404, lowers PCBP2 transcription and protein levels, reduces condensates, decreases BACE1 and Aβ, and improves cognitive performance in 5×FAD mice Conclusion:Targeting PCBP2 biomolecular condensates via INTS1 with CN-0928 offers a novel strategy to mitigate mitochondrial dysfunction and BACE1-driven amyloidogenesis in Alzheimer’s disease Music:Enjoy the music based on this article at the end of the episode. Reference:Wang L, Xie X-Y, Pan Q-L, Zhang J, Zhou G-F, Zhang Q-L, Yan X-X, Xiang Y, Li C-L, He Y, Xiang X-J, Deng X-J, Wang Y-J, Zhou J-Y, Nie S & Chen G-J. Pharmacologic inhibition of PCBP2 biomolecular condensates relieves Alzheimer’s disease. Nat Commun. 2025;16:10514. https://doi.org/10.1038/s41467-025-65547-9 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com Castos player https://basebybase.castos.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.castos.com/episodes/pcbp2-condensates-alzheimers Episode Slug: pcbp2-condensates-alzheimers Keywords: PCBP2, biomolecular condensates, BACE1, CN-0928, mitochondria

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