Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Cell Metab. 2018 Oct 2;28(4):605-618.e6. doi: 10.1016/j.cmet.2018.05.019. Epub 2018 Jun 14.
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.
PLA2G6（PARK14）中的突变会导致人类神经退行性疾病，包括常染色体隐性遗传性轴索神经病和早发性帕金森病。我们发现，iPLA2-VIA（PLA2G6 的果蝇同源物）的缺失会缩短寿命、损害突触传递，并导致神经退行性病变。磷脂酶通常水解甘油磷脂，但 iPLA2-VIA 的缺失并不会影响脑组织的磷脂组成，而是导致神经酰胺的升高。用药物（包括霉菌酸或去甲丙咪嗪）降低神经酰胺水平，可以缓解溶酶体应激并抑制神经退行性病变。iPLA2-VIA 与 retromer 亚基 Vps35 和 Vps26 结合，并增强 retromer 的功能，促进蛋白质和脂质的再循环。iPLA2-VIA 的缺失会损害 retromer 的功能，导致神经酰胺的逐渐增加。这会引发一个正反馈循环，影响膜流动性并损害 retromer 功能和神经元功能。在 vps26 或 vps35 缺失或α-突触核蛋白过表达时也观察到类似的缺陷，这表明这些缺陷在帕金森病中可能很常见。
