Mutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD)—collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease-linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a “pathological package” capable of inducing aggregation of wild-type alpha-synuclein, mediated through a combination of alpha-synuclein–ceramide interaction and the presence of pathological forms of alpha-synuclein. Together, our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency.

葡糖脑苷脂酶 ( GBA ) 突变是路易体疾病 (LBD) 最普遍的遗传风险因素 - 统称为帕金森病、帕金森病痴呆和路易体痴呆。尽管存在这种遗传关联，但尚不清楚GBA突变如何增加 LBD 的易感性。我们研究了 LBD 和对照组脑组织中 LBD 特异性葡萄糖脑苷脂酶缺陷、GBA 相关通路和 α-突触核蛋白水平之间的关系，有无GBA突变。我们表明 LBD 的特征是鞘脂代谢改变，神经酰胺种类显着升高，与GBA无关突变。由于细胞外囊泡 (EV) 可通过传播与疾病相关的脂质和蛋白质参与 LBD 发病机制，我们研究了源自死后脑脊液 (CSF) 和GBA脑组织的 EV突变携带者和非携带者。从 LBD CSF 和额叶皮层纯化的 EV 富含神经酰胺和神经退行性相关蛋白，包括 α-突触核蛋白和 tau。我们的体外研究表明，LBD EV 构成了一个“病理包”，能够诱导野生型 α-突触核蛋白聚集，通过 α-突触核蛋白-神经酰胺相互作用和病理形式的 α-突触核蛋白的存在介导。总之，我们的研究结果表明神经酰胺代谢异常是 LBD 的一个特征，构成了一个有希望的生物标志物来源，并且GBA突变可能通过内溶酶体缺乏加速散发性 LBD 中发生的病理过程。