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Prion-like α-synuclein pathology in the brain of infants with Krabbe disease

journal contribution
submitted on 2024-04-22, 10:08 and posted on 2024-04-22, 10:09 authored by Christopher Hatton, Simona S. Ghanem, David J. Koss, Ilham Y. Abdi, Elizabeth Gibbons, Rita Guerreiro, Jose Bras, Celia Kun-Rodrigues, Andrew Singleton, Dena Hernandez, Owen A. Ross, Dennis W. Dickson, Neill Graff-Radford, Tanis J. Ferman, Ronald C. Petersen, Brad F. Boeve, Michael G. Heckman, John Q. Trojanowski, Vivianna Van Deerlin, Nigel J. Cairns, John C. Morris, David J. Stone, John D. Eicher, Lorraine Clark, Lawrence S Honig, Karen Marder, Geidy E. Serrano, Thomas G. Beach, Douglas Galasko, Eliezer Masliah, John Hardy, Lee Darwent, Olaf Ansorge, Laura Parkkinen, Kevin Morgan, Kristelle Brown, Anne Braae, Imelda Barber, Claire Troakes, Safa Al-Sarraj, Tom Warner, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Tamas Revesz, Andrew Lees, Henrik Zetterberg, Valentina Escott-Price, Stuart Pickering-Brown, David Mann, Peter St. George-Hyslop, Ekaterina Rogaeva, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Pau Pastor, Monica Diez-Fairen, Miquel Aquilar, Claire Shepherd, Glenda M. Halliday, Pentti J. Tienari, Liisa Myllykangas, Minna Oinas, Isabel Santana, Suzanne Lesage, Elisabet Londos, Afina Lemstra, Lauren Walker, Ellen Gelpi, Wendy Heywood, Tiago F. Outeiro, Johannes Attems, Robert McFarland, Rob Forsyth, Omar M. El-Agnaf, Daniel Erskine, International DLB Genetics Consortium

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.

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Published in: Brain
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  • English


Oxford University Press

Publication Year

  • 2022

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This Item is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License

Institution affiliated with

  • Hamad Bin Khalifa University
  • Qatar Biomedical Research Institute - HBKU
  • Neurological Disorders Research Center - QBRI

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