Fibrillary aggregation of alpha-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 alpha-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 alpha-synuclein aggregation into Lewy body-like inclusions, and the reduction of glucocerebrosidase activity accelerated alpha-synuclein pathology by promoting fibrillary alpha-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 alpha-synuclein pathology in this model, supporting the use of midbrain organoids as a relevant preclinical platform for investigational drug screening.Frattini et al. present a new human iPSC-derived midbrain organoid model for the study of Parkinson's disease. The midbrain organoids contain mature dopaminergic neurons with nigrostriatal-like characteristics, and reproduce key signatures of Lewy pathology observed in the human brain.
Lewy pathology formation in patient-derived GBA1 Parkinson’s disease midbrain organoids
Solda', Giulia;Straniero, Letizia;Facchi, Daniele;Asselta, Rosanna;
2025-01-01
Abstract
Fibrillary aggregation of alpha-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 alpha-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 alpha-synuclein aggregation into Lewy body-like inclusions, and the reduction of glucocerebrosidase activity accelerated alpha-synuclein pathology by promoting fibrillary alpha-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 alpha-synuclein pathology in this model, supporting the use of midbrain organoids as a relevant preclinical platform for investigational drug screening.Frattini et al. present a new human iPSC-derived midbrain organoid model for the study of Parkinson's disease. The midbrain organoids contain mature dopaminergic neurons with nigrostriatal-like characteristics, and reproduce key signatures of Lewy pathology observed in the human brain.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
