Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease.

Autor:	Gojanovich AD; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA., Le NTT; Department of Biochemistry & Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Mercer RCC; Department of Biochemistry & Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Park S; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA., Wu B; Department of Biochemistry & Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Anane A; Creutzfeldt-Jakob Disease Foundation, Pardes Hanna-Karkur, Israel., Vultaggio JS; Department of Biochemistry & Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA., Mostoslavsky G; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA; Department of Microbiology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA; Department of Medicine, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA. Electronic address: gmostosl@bu.edu., Harris DA; Department of Biochemistry & Cell Biology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA. Electronic address: daharris@bu.edu.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2024 Oct 08; Vol. 19 (10), pp. 1474-1488. Date of Electronic Publication: 2024 Sep 26.
DOI:	10.1016/j.stemcr.2024.08.010
Abstrakt:	Genetic prion diseases are caused by mutations in PRNP, which encodes the prion protein (PrP C ). Why these mutations are pathogenic, and how they alter the properties of PrP C are poorly understood. We have consented and accessed 22 individuals of a multi-generational Israeli family harboring the highly penetrant E200K PRNP mutation and generated a library of induced pluripotent stem cells (iPSCs) representing nine carriers and four non-carriers. iPSC-derived neurons from E200K carriers display abnormal synaptic architecture characterized by misalignment of postsynaptic NMDA receptors with the cytoplasmic scaffolding protein PSD95. Differentiated neurons from mutation carriers do not produce PrP Sc , the aggregated and infectious conformer of PrP, suggesting that loss of a physiological function of PrP C may contribute to the disease phenotype. Our study shows that iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases and can offer a powerful platform for testing candidate therapeutics. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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