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ResearchIn-Press PreviewCell biologyDevelopmentNeuroscience
Open Access | 
10.1172/JCI196452
Nucleocytoplasmic shuttling of USP15 promotes pathological autophagy that disrupts neural stem cell homeostasis and neurodevelopment
Kaylan M.L. Burns,1 Mashiat Zaman,1 Daniel Young,2 Michelle Hua,1 Yu-Yun Gao,1 Yvonne Yan Yan Or,3 Farzaneh Nobakht,1 Bryn D. Webb,4 Julie A. Jurgens,5 Francis Ramond,6 Xing-Chang Wei,7 Caroline D. Robson,8 Alistair T. Pagnamenta,9 Marvel Megaly,3 Belal Tafech,3 Antoine Dufour,2 Timothy E. Shutt,1 Ping Yee Billie Au,10 and Guang Yang3
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Burns, K. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Zaman, M. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Young, D. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Hua, M. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Gao, Y. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
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1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Nobakht, F. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
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1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
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1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
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1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Wei, X. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
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1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
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1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Megaly, M. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Tafech, B. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
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1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Shutt, T. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Au, P. in: PubMed | Google Scholar
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Canada
2Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada
3Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada
4Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, United States of America
5Department of Neurology, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, United States of America
6Department of Genetics, Saint-Étienne University Hospital, Saint-Étienne, France
7Diagnostic Imaging, Alberta Children’s Hospital, Calgary, Canada
8Department of Radiology, Boston Children’s Hospital and Harvard University, Boston, United States of America
9Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
10Department of Medical Genetics, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Canada
Find articles by Yang, G. in: PubMed | Google Scholar
Published October 6, 2026 - More info
Copyright © 2026, Burns 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/.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)