ArticleBrain : a journal of neurology2025
Lewy pathology formation in patient-derived GBA1 Parkinson's disease midbrain organoids.
Article in Brain : a journal of neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Organoids: Key advances, optimization, and technological iterations in their application to neurodegenerative diseases.Neural regeneration research · 2026Article
- Interplay of GBA1 with lysosomal dysfunction and inflammation in Parkinson's disease.Neural regeneration research · 2026Article
- When Pathologies Collide: The Intersection of Tau and Alpha-Synuclein in Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- Rethinking Mitochondrial Parkinson's Disease in the α-Synuclein Seed Amplification Assays Era.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Next-Generation Strategies for Neural Repair and Regeneration: Neural Organoid Transplantation in the CNS.Cell proliferation · 2026Review
- Regulation of Tau Alternative Splicing: A Novel Role for the Ribonucleoprotein RBM20.International journal of molecular sciences · 2026Article
- Advances in the pathophysiological study of brain development: application of cerebral organoid combined with Spatial omics technology.Stem cell research & therapy · 2026Review
- Propagation of α-synuclein pathology: models, mechanisms and future goals.Molecular neurodegeneration advances · 2026Review
- Underlying Mechanisms of GBA1 in Parkinson's Disease and Dementia with Lewy Bodies: Narrative Review.Genes · 2025Review
- Dysregulated proteostasis in p.A53T-α-Synuclein astrocytes aggravates Lewy-like neuropathology in a Parkinson's disease iPSC model.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Investigating the ageing-Parkinson's disease nexus: standardisation of in vitro models and techniques by the PD-AGE network.NPJ Parkinson's disease · 2025Review
- Bioelectronic Interfaces and Sensors for Neural Organoids.Microsystems & nanoengineering · 2025Review
- Review
- Drug discovery and development for Parkinson's disease: are preclinical models good enough?Frontiers in aging neuroscience · 2025Review
- Exercise modulation of BDNF/TrkB signaling in Parkinson's disease: an evidence-calibrated review of neuroprotective mechanisms, biomarker limitations, and translational gaps.Frontiers in neurologyReview
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33 authors.
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Abstract
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.
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