Lewy pathology formation in patient-derived <i>GBA1</i> Parkinson’s disease midbrain organoids
Fibrillary aggregation of α-synuclein in Lewy body inclusions and nigrostriatal dopaminergic neuron degeneration define Parkinson's disease neuropathology. Mutations in GBA1, encoding glucocerebrosidase, are the most frequent genetic risk factor for Parkinson's disease. However, the lack of reliable experimental models able to reproduce key neuropathological signatures has hampered clarification of the link between mutant glucocerebrosidase and Parkinson's disease pathology. Here, we describe an innovative protocol for the generation of human induced pluripotent stem cell-derived midbrain organoids containing dopaminergic neurons with nigral identity that reproduce characteristics of advanced maturation. When applied to patients with GBA1-related Parkinson's disease, this method enabled the differentiation of midbrain organoids recapitulating dopaminergic neuron loss and fundamental features of Lewy pathology observed in human brains, including the generation of α-synuclein fibrillary aggregates with seeding activity that also propagate pathology in healthy control organoids. Concurrently, we found that the retention of mutant glucocerebrosidase in the endoplasmic reticulum and increased levels of its substrate, glucosylceramide, are determinants of α-synuclein aggregation into Lewy body-like inclusions, and the reduction of glucocerebrosidase activity accelerated α-synuclein pathology by promoting fibrillary α-synuclein deposition. Finally, we demonstrated the efficacy of ambroxol and GZ667161 (two modulators of the glucocerebrosidase pathway in clinical development for the treatment of GBA1-related Parkinson's disease) in reducing α-synuclein pathology in this model, supporting the use of midbrain organoids as a relevant preclinical platform for investigational drug screening.
Authors
- Manuela Magni (ORCID: https://orcid.org/0000-0002-2016-3574)
- Ilaria Trezzi (ORCID: https://orcid.org/0000-0002-0177-1021)
- Emma V Carsana
- Fabio Blandini (ORCID: https://orcid.org/0000-0002-0178-1289)
- Maura Samarani (ORCID: https://orcid.org/0000-0002-6376-5524)
- Arianna Bellucci (ORCID: https://orcid.org/0000-0002-9581-1919)
- Chiara Maria Giulia De Luca (ORCID: https://orcid.org/0000-0002-6233-8272)
- Rosanna Asselta (ORCID: https://orcid.org/0000-0001-5351-0619)
- Gaia Faustini (ORCID: https://orcid.org/0000-0002-0751-3082)
- S. Pablo Sardi (ORCID: https://orcid.org/0000-0001-9805-3677)
- Astghik Stepanyan (ORCID: https://orcid.org/0009-0002-0323-0955)
- Rosamaria Silipigni
- Giacomo P. Comi (ORCID: https://orcid.org/0000-0002-1383-5248)
- Gianluca Lopez (ORCID: https://orcid.org/0000-0002-9262-1212)
- Letizia Straniero (ORCID: https://orcid.org/0000-0002-1733-7561)
- Elena Vezzoli (ORCID: https://orcid.org/0000-0002-3342-3451)
- Fulvia Milena Cribiù
- Nicolas X. Tritsch (ORCID: https://orcid.org/0000-0003-3181-7681)
- Giulia Soldà (ORCID: https://orcid.org/0000-0003-0972-610X)
- Daniele Facchi
- Isabel Rosety (ORCID: https://orcid.org/0000-0001-9118-6995)
- Fabio Moda (ORCID: https://orcid.org/0000-0002-2820-9880)
- Thomas Wısnıewskı (ORCID: https://orcid.org/0000-0002-3379-8966)
- Jens C. Schwamborn (ORCID: https://orcid.org/0000-0003-4496-0559)
- Mario Bortolozzi (ORCID: https://orcid.org/0000-0001-7198-9838)
- Alessio Di Fonzo (ORCID: https://orcid.org/0000-0001-6478-026X)
- Emanuele Frattini (ORCID: https://orcid.org/0000-0002-5375-2404)
- Massimo Aureli (ORCID: https://orcid.org/0000-0003-1916-2440)
- Alessandra Pittaro
- Mitchell Martá-Ariza (ORCID: https://orcid.org/0000-0002-2121-7685)
- Mattia Tosi
- Stefania Corti
- Stefano Ferrero
Institutions
- Universitat Autònoma de Barcelona (ES)
- Humanitas University (IT)
- University of Padua (IT)
- Vita-Salute San Raffaele University (IT)
- Institut Pasteur (FR)
- University of Luxembourg (LU)
- University of Milan (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Sanofi (France) (FR)
- Brescia University (US)
- NYU Langone Health (US)
- Ospedale Maggiore (IT)
- Veneto Institute of Molecular Medicine (IT)
- Sanofi (United States) (US)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Ferrari (Italy) (IT)
- IRCCS Humanitas Research Hospital (IT)
- Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
- Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT)
- New York University (US)
- University of Brescia (IT)
Publication Details
- Journal
- Brain
- Published
- 2024-11-19
- DOI
- https://doi.org/10.1093/brain/awae365
- Citations
- 14
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 5.17