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ResearchIn-Press PreviewGeneticsMetabolismNeuroscience Open Access | 10.1172/JCI199140

Proteasome mutations associated with CANDLE syndrome cause altered neuronal development by dysregulating polyamine synthesis

Clayton W. Winkler,1 Benjamin Schwarz,2 Katie Williams,3 Sara Alehashemi,4 Simote T. Foliaki,3 Joseph Snow,5 Lisa Joseph,6 Audrey Thurm,6 Christopher L. Friend,4 Gwendolyn Cooper,2 Eric Bohrnsen,2 Farzana Bhuyan,4 Nathan T. Brandes,2 Ruin Moaddel,7 Manfred Boehm,8 Guibin Chen,8 Cole D. Kimzey,2 Bibiana Bielekova,9 Joanna Kocot,9 Peter Kosa,9 Cathryn L. Haigh,3 Raphaela Goldbach-Mansky,4 and Karin E. Peterson1

1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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1Neuroimmunology Section, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

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

3Prion Cell Biology Unit, Laboratory of Neurological Infections and Immunity, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, NIH, Hamilton, United States of America

4Translational Autoinflammatory Diseases Section, Laboratory of Clinical Imm, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

5Neuropsychology Consult Service, Intramural Research Program, National Institute of Mental Health, NIH, Bethesda, United States of America

6Neurodevelopmental and Behavioral Phenotyping Service, Intramural Research , National Institute of Mental Health, NIH, Bethesda, United States of America

7Laboratory of Clinical Investigation, Biomedical Research Center, National Institute on Aging, NIH, Baltimore, United States of America

8Laboratory of Cardiovascular Regenerative Medicine, Translational Vascular , National Heart, Lung, and Blood Institute, NIH, Bethesda, United States of America

9Neuroimmunological Diseases Section, Laboratory of Clinical Immunology & Mi, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, United States of America

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Published August 4, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI199140.
Copyright © 2026, Winkler 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 August 4, 2026 - Version history
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Abstract

Loss-of-function mutations in PSMB8/beta5i and other components of the 20S proteasome result in multi-organ diseases, such as Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. Neurocognitive dysfunction associated with CANDLE suggests that proteasomal mutations may impact neuronal function and development early in life. We generated cerebral organoids (COs) from induced pluripotent stem cells (iPSCs) made from CANDLE patients. The COs from CANDLE iPSCs exhibited impaired neuronal development when compared to COs from healthy control iPSCs. Impaired neuronal maturation in CANDLE COs was correlated with increased polyamines, which were also elevated in CANDLE patient CSF. The proteasome-regulated Ornithine decarboxylase (ODC), the rate limiting enzyme in polyamine biosynthesis, was elevated in CANDLE neurons. Inhibition of ODC reversed polyamine overproduction and repaired neuronal maturation in CANDLE COs, suggesting a potential therapeutic avenue for intervention. These findings demonstrate that dysfunction of the proteasome affects neuronal development through overproduction of polyamines via dysregulation of ODC and offer insight into potential therapeutic strategies for CNS-related proteasomal dysfunction.

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  • Version 1 (August 4, 2026): In-Press Preview
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