Parkinson's disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.

中文翻译：

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ATP10B突变通过损害溶酶体葡萄糖神经酰胺输出而增加了帕金森氏病的风险。

帕金森氏病（PD）是一种进行性神经退行性脑疾病，表现为多种运动和非运动症状，黑质致密部中脑多巴胺能神经元缺失以及存活的神经元中α-突触核蛋白阳性路易体的出现。在这里，我们对52位早发性PD患者进行了完整的外显子组测序，并确定了ATP10B P4型ATPase基因中3个复合杂合突变的携带者。对比利时PD和痴呆伴有路易小体（DLB）的人群进行遗传筛选，发现了另外4种复合杂合突变携带者（6/617 PD患者，0.97％； 1/226 DLB患者，0.44％）。我们建立了ATP10B编码晚期溶酶体脂质脂酶的功能，该酶将脂质葡糖神经酰胺（GluCer）和磷脂酰胆碱（PC）移向胞质膜小叶。与PD相关的ATP10B突变体具有催化活性，不能针对环境PD危险因素鱼藤酮和锰提供细胞保护。在分离的皮质神经元中，ATP10B的缺失会导致一般的溶酶体功能障碍和细胞死亡。众所周知，溶酶体功能和完整性受损与PD病理学有关，并与多个因果PD基因和遗传危险因素有关。我们的研究结果表明，ATP酶B10B功能突变的隐性丧失会通过干扰GluCer和PC的溶酶体输出而增加PD的风险。PD风险基因GBA1编码的ATP10B和葡萄糖脑苷脂酶1均降低了溶酶体GluCer水平，使溶酶体GluCer积累成为潜在的PD驱动因素。