IRCCS Humanitas Research Hospital & Humanitas University
Published October 28, 2021 | Version v1
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Dataset related to article "Parkinson's disease midbrain organoids link GBA1 to Lewy pathology"

Authors/Creators

  • 1. Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
  • 2. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
  • 3. Division of Pathology, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
  • 4. Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, LITA Segrate, Milano, Italy
  • 5. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele-Milan, Italy
  • 6. Unité de Trafic Membranaire et Pathogénèse, Département de Biologie Cellulaire et de l'Infection, Institut Pasteur, Paris, France
  • 7. Luxembourg Centre for Systems Biomedicine (LCSB), Developmental and Cellular Biology, University of Luxembourg, Belvaux, Luxembourg
  • 8. Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, NY, USA
  • 9. Division of Neurology 5 and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
  • 10. Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
  • 11. Chirurgia Generale 3, University Hospital of Padua, Padua, Italy
  • 12. IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Laboratorio di Genetica Medica, Milan, Italy
  • 13. Rare and Neurological Diseases Therapeutic Area, Sanofi, Framingham, Massachusetts, USA
  • 14. Neuroscience Institute, New York University Grossman School of Medicine, New York, NY, USA
  • 15. Department of Physics and Astronomy "G. Galilei", Padua, Italy; Veneto Institute of Molecular Medicine (VIMM), Padua, Italy
  • 16. Department of Biomedical, Surgical, and Dental Sciences, University of Milan, 20122 Milan, Italy
  • 17. Department of Pathology and Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA

Description

This record contains data related to the article "Parkinson’s disease midbrain organoids link GBA1 to Lewy pathology".

Abstract

Aggregation of α-synuclein protein in “Lewy bodies” or “Lewy neurites” is a defining hallmark of Parkinson’s disease neuropathology. Mutations in GBA1, encoding the glucosylceramide-hydrolyzing enzyme glucocerebrosidase, cause Gaucher’s disease and are the most frequent genetic risk factor for Parkinson’s disease. However, a defined link between mutations in GBA1 and α-synuclein pathology is yet to be determined, largely because of the absence of experimental models able to recapitulate the key neuropathological signatures of the disease. Here, we present an innovative midbrain organoid culture system derived from subjects with GBA1-related Parkinson’s disease as the first patient-based model able to reproduce fundamental neuropathological features of the disease. We show that retention of mutant glucocerebrosidase in the endoplasmic reticulum and increased glucosylceramide levels are determinants of α-synuclein aggregation into inclusions resembling Lewy bodies and Lewy neurites in both mono- and biallelic GBA1 mutated midbrain organoids. In this process, the entity of glucocerebrosidase activity reduction acts as an accelerating factor in the progression of α-synuclein pathology by favoring the conversion of soluble α-synuclein to its insoluble forms. We provide evidence that α-synuclein extracted from Parkinson’s samples displays seeding activity in vitro and, following inoculation in unaffected organoids, propagates the pathology. Finally, we demonstrate pharmacological rescue of pathological phenotypes with molecules engaging in the glucocerebrosidase pathway, suggesting that midbrain organoids could represent valuable in vitro platforms for drug testing in Parkinson’s disease and potentially other Lewy body disorders still lacking a definitive therapy.

 

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