Dataset related to article "Parkinson's disease midbrain organoids link GBA1 to Lewy pathology"

<p>This record contains data related to the article&nbsp;&quot;Parkinson&rsquo;s disease midbrain organoids link GBA1 to Lewy pathology&quot;.</p> <p><strong>Abstract</strong></p> <p>Aggregation of &alpha;-synuclein protein in &ldquo;Lewy bodies&rdquo; or &ldquo;Lewy neurites&rdquo; is a defining hallmark of Parkinson&rsquo;s disease neuropathology. Mutations in&nbsp;<em>GBA1</em>, encoding the glucosylceramide-hydrolyzing enzyme glucocerebrosidase, cause Gaucher&rsquo;s disease and are the most frequent genetic risk factor for Parkinson&rsquo;s disease. However, a defined link between mutations in&nbsp;<em>GBA1</em>&nbsp;and &alpha;-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.&nbsp;Here, we present an innovative midbrain organoid culture system derived from subjects with&nbsp;<em>GBA1</em>-related Parkinson&rsquo;s disease as the first patient-based model able to reproduce fundamental neuropathological features of the disease. We show that retention of&nbsp;mutant glucocerebrosidase in the endoplasmic reticulum and increased glucosylceramide levels are determinants of&nbsp;&alpha;-synuclein aggregation&nbsp;into inclusions resembling Lewy bodies and Lewy neurites in both&nbsp;mono- and biallelic&nbsp;<em>GBA1</em>&nbsp;mutated midbrain organoids.&nbsp;In this process, the entity of glucocerebrosidase activity reduction acts as an accelerating factor in the progression of&nbsp;&alpha;-synuclein&nbsp;pathology by favoring the conversion of soluble&nbsp;&alpha;-synuclein&nbsp;to its insoluble forms. We provide evidence that &alpha;-synuclein extracted from Parkinson&rsquo;s samples displays seeding activity&nbsp;<em>in vitro</em>&nbsp;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&nbsp;<em>in vitro</em>&nbsp;platforms for drug testing in Parkinson&rsquo;s disease and potentially other Lewy body disorders still lacking a definitive therapy.</p> <p>&nbsp;</p>