Advertisement

ResearchIn-Press PreviewCell biologyInfectious diseaseNeuroscience Open Access | 10.1172/JCI194721

Distinct neuronal alterations distinguish two subtypes of sporadic Creutzfeldt-Jakob disease with shared dysfunctional pathways

Katie Williams,1 Bradley R. Groveman,1 Simote T. Foliaki,1 Brent Race,1 Arielle Hay,1 Ryan O. Walters,1 Tina Thomas,2 Gianluigi Zanusso,3 James A. Carroll,1 and Cathryn L. Haigh1

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Williams, K. in: PubMed | Google Scholar

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Groveman, B. in: PubMed | Google Scholar

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Foliaki, S. in: PubMed | Google Scholar

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Race, B. in: PubMed | Google Scholar

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Hay, A. in: PubMed | Google Scholar

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Walters, R. in: PubMed | Google Scholar

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Thomas, T. in: PubMed | Google Scholar

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Zanusso, G. in: PubMed | Google Scholar

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Carroll, J. in: PubMed | Google Scholar

1Division of Intramural Research, Laboratory of Neurological Infections and , National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

2Rocky Mountain Veterinary Branch, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, NIH, Hamilton, United States of America

3Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy

Find articles by Haigh, C. in: PubMed | Google Scholar

Published February 12, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI194721.
Copyright © 2026, Williams et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 12, 2026 - Version history
View PDF
Abstract

Prion diseases are a family of transmissible, neurodegenerative conditions caused by mis-folded proteins called prions. Human cerebral organoids can be infected with prions from sporadic Creutzfeldt-Jakob Disease (sCJD) brain tissue. Initial experiments indicated that the cerebral organoids may be able to differentiate biological properties of different sCJD subtypes and, if so, it would be possible to investigate the pathogenic similarities and differences. Herein, we investigated multiple infections of cerebral organoids with two sCJD subtypes, comparing hallmark features of disease as well as neuronal function and health. Our results show that while all infections produced seeding capable PrP, which increased from 90-180 days post infection, a sCJD subtype preference for protease resistant PrP deposition was observed. Both subtypes caused substantial electrophysiological dysfunction in the infected organoids, which appeared uncoupled from PrP deposition. Neuronal dysfunction was associated with changes in neurotransmitter receptors that differed between the subtypes but produced the same outcome of a shift from inhibitory toward excitatory neurotransmission. Further changes indicated shared deficits in mitochondrial dynamics, and subtype influenced alterations in intracellular signaling pathways, cytoskeletal structure, and the extracellular matrix. We conclude that cerebral organoids demonstrate both common mitochondrial deficits and sCJD subtype specific changes in neurotransmission and organoid architecture.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

View Supplementary File 6

View Supplementary File 12

View Supplementary File 13

View Supplementary File 16

Version history
  • Version 1 (February 12, 2026): In-Press Preview
Advertisement
Advertisement