Dataset related to article "Parkinson's disease midbrain organoids link GBA1 to Lewy pathology"
<p>This record contains data related to the article "Parkinson’s disease midbrain organoids link GBA1 to Lewy pathology".</p> <p><strong>Abstract</strong></p> <p>Aggregation of α-synuclein protein in “Lewy bodies” or “Lewy neurites” is a defining hallmark of Parkinson’s disease neuropathology. Mutations in <em>GBA1</em>, 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 <em>GBA1</em> 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 <em>GBA1</em>-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 <em>GBA1</em> 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 <em>in vitro</em> 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 <em>in vitro</em> platforms for drug testing in Parkinson’s disease and potentially other Lewy body disorders still lacking a definitive therapy.</p> <p> </p>
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