Prion-like α-synuclein pathology in the brain of infants with Krabbe disease
Author:
Hatton Christopher12, Ghanem Simona S.3, Koss David J.2ORCID, Abdi Ilham Y.3, Gibbons Elizabeth4, Guerreiro Rita45, Bras Jose45, Bras Jose, Guerreiro Rita, Kun-Rodrigues Celia, Singleton Andrew, Hernandez Dena, Ross Owen A., Dickson Dennis W., Graff-Radford Neill, Ferman Tanis J., Petersen Ronald C., Boeve Brad F., Heckman Michael G., Trojanowski John Q., Van Deerlin Vivianna, Cairns Nigel J., Morris John C., Stone David J., Eicher John D., Clark Lorraine, Honig Lawrence S, Marder Karen, Serrano Geidy E., Beach Thomas G., Galasko Douglas, Masliah Eliezer, Hardy John, Darwent Lee, Ansorge Olaf, Parkkinen Laura, Morgan Kevin, Brown Kristelle, Braae Anne, Barber Imelda, Troakes Claire, Al-Sarraj Safa, Warner Tom, Lashley Tammaryn, Holton Janice, Compta Yaroslau, Revesz Tamas, Lees Andrew, Zetterberg Henrik, Escott-Price Valentina, Pickering-Brown Stuart, Mann David, George-Hyslop Peter St., Rogaeva Ekaterina, George-Hyslop Peter St., Clarimon Jordi, Lleo Alberto, Morenas-Rodriguez Estrella, Pastor Pau, Diez-Fairen Monica, Aquilar Miquel, Compta Yaroslau, Shepherd Claire, Halliday Glenda M., Tienari Pentti J., Myllykangas Liisa, Oinas Minna, Santana Isabel, Lesage Suzanne, Zetterberg Henrik, Londos Elisabet, Lemstra Afina, Walker Lauren2, Gelpi Ellen6, Heywood Wendy7, Outeiro Tiago F.28910, Attems Johannes2, McFarland Robert1211, Forsyth Rob211, El-Agnaf Omar M.3, Erskine Daniel12ORCID,
Affiliation:
1. Wellcome Centre for Mitochondrial Research, Claremont Road, Newcastle NE2 4AA, UK 2. Translational and Clinical Research Institute, Newcastle University, Newcastle NE2 4AA, UK 3. Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar 4. Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA 5. Division of Psychiatry and Behavioral Medicine, Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA 6. Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria 7. UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK 8. Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073 Göttingen, Germany 9. Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany 10. Scientific employee with an honorary contract at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 37075 Göttingen, Germany 11. Department of Paediatric Neurology, Great North Children’s Hospital, Newcastle NE1 4LP, UK
Abstract
Abstract
Krabbe disease is an infantile neurodegenerative disorder resulting from pathogenic variants in the GALC gene that causes accumulation of the toxic sphingolipid psychosine. GALC variants are also associated with Lewy body diseases, an umbrella term for age-associated neurodegenerative diseases in which the protein α-synuclein aggregates into Lewy bodies. To explore whether α-synuclein in Krabbe disease has pathological similarities to that in Lewy body disease, we performed an observational post-mortem study of Krabbe disease brain tissue (n = 4) compared to infant controls (n = 4) and identified widespread accumulations of α-synuclein. To determine whether α-synuclein in Krabbe disease brain displayed disease-associated pathogenic properties we evaluated its seeding capacity using the real-time quaking-induced conversion assay in two cases for which frozen tissue was available and strikingly identified aggregation into fibrils similar to those observed in Lewy body disease, confirming the prion-like capacity of Krabbe disease-derived α-synuclein. These observations constitute the first report of prion-like α-synuclein in the brain tissue of infants and challenge the putative view that α-synuclein pathology is merely an age-associated phenomenon, instead suggesting it results from alterations to biological pathways, such as sphingolipid metabolism. Our findings have important implications for understanding the mechanisms underlying Lewy body formation in Lewy body disease.
Funder
Alzheimer’s Research UK Northern Network Qatar Biomedical Research Institute South Tees Hospitals NHS Foundation Trust Lewy Body Society Deutsche Forschungsgemeinschaft German Research Foundation NHS NIHR Department of Health
Publisher
Oxford University Press (OUP)
Subject
Neurology (clinical)
Cited by
7 articles.
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