Mutations in PLA2G6 (PARK14) cause neurodegenerative disorders in humans, including autosomal recessive neuroaxonal dystrophy and early-onset parkinsonism. We show that loss of iPLA2-VIA, the fly homolog of PLA2G6, reduces lifespan, impairs synaptic transmission, and causes neurodegeneration. Phospholipases typically hydrolyze glycerol phospholipids, but loss of iPLA2-VIA does not affect the phospholipid composition of brain tissue but rather causes an elevation in ceramides. Reducing ceramides with drugs, including myriocin or desipramine, alleviates lysosomal stress and suppresses neurodegeneration. iPLA2-VIA binds the retromer subunits Vps35 and Vps26 and enhances retromer function to promote protein and lipid recycling. Loss of iPLA2-VIA impairs retromer function, leading to a progressive increase in ceramide. This induces a positive feedback loop that affects membrane fluidity and impairs retromer function and neuronal function. Similar defects are observed upon loss of vps26 or vps35 or overexpression of α-synuclein, indicating that these defects may be common in Parkinson disease.

中文翻译：

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与帕金森氏症相关的基因磷脂酶PLA2G6对Vps26和Vps35，逆转录酶功能和神经酰胺水平的影响与α-突触核蛋白增益相似。

PLA2G6（PARK14）中的突变会导致人类神经退行性疾病，包括常染色体隐性神经轴索营养不良和早发性帕金森病。我们表明损失的iPLA2-VIA，PLA2G6的蝇同源物，减少寿命，损害突触传递，并引起神经退行性变。磷脂酶通常会水解甘油磷脂，但iPLA2-VIA的损失不会影响脑组织的磷脂成分，而会导致神经酰胺的升高。用包括myriocin或desipramine在内的药物还原神经酰胺可减轻溶酶体压力并抑制神经退行性变。iPLA2-VIA结合了逆转子亚基Vps35和Vps26，并增强了逆转子功能，以促进蛋白质和脂质的循环利用。iPLA2-VIA的丧失会损害逆转录酶功能，导致神经酰胺的逐步增加。这引起了影响膜流动性并损害后体功能和神经元功能的正反馈回路。在vps26或vps35缺失或α-突触核蛋白过表达时观察到类似的缺陷，表明这些缺陷可能在帕金森氏病中很常见。