MODELLING GBA1-RELATED PARKINSON¿S DISEASE PATHOLOGY IN PATIENT-DERIVED MIDBRAIN ORGANOIDS

Aggregation of α-synuclein protein in “Lewy bodies” and “Lewy neurites” and dopaminergic neuronal loss in the nigrostriatal system are the key neuropathological hallmarks of Parkinson’s disease. 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 Parkinson’s disease pathology is yet to be determined, largely because of the absence of experimental models able to recapitulate the defining neuropathological signatures of the disease. Here, we present an innovative midbrain organoid culture system derived from subjects with GBA1-related Parkinson’s disease and Gaucher’s disease as the first patient-based model able to reproduce fundamental human neuropathological features of these disorders. We provide evidence of glucosylceramide accumulation due to glucocerebrosidase deficiency and, notably, of insoluble α-synuclein aggregation in inclusions reminiscent of Lewy bodies and Lewy neurites in GBA1-mutated organoids. We show 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, 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.