Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy; Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA, United States.
Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genoa, Italy.
Adv Pharmacol. 2021;90:217-238. doi: 10.1016/bs.apha.2020.09.003. Epub 2020 Oct 6.
N-acylphosphatidylethanolamines (NAPEs) are glycerophospholipid precursors for bioactive lipid amides and potential regulators of membrane function. They are hydrolyzed by NAPE-specific phospholipase D (NAPE-PLD) and have been implicated in neurodegenerative disorders such as Parkinson's disease. Here, we used siRNA-mediated silencing of NAPE-PLD in human SH-SY5Y cells and NAPE-PLD mice to determine whether NAPEs influence the membrane association of LRRK2, a multifunctional protein kinase that is frequently mutated in persons with sporadic Parkinson's disease. NAPE-PLD deletion caused a significant accumulation of non-metabolized NAPEs, which was accompanied by a shift of LRRK2 from membrane to cytosol and a reduction in total LRRK2 content. Conversely, exposure of intact SH-SY5Y cells to bacterial PLD lowered NAPE levels and enhanced LRRK2 association with membranes. The results suggest that NAPE-PLD activity may contribute to the control of LRRK2 localization by regulating membrane NAPE levels.
N-酰基磷脂酰乙醇胺 (NAPEs) 是生物活性脂质酰胺的甘油磷脂前体，也是膜功能的潜在调节剂。它们被 NAPE 特异性磷脂酶 D (NAPE-PLD) 水解，并与神经退行性疾病如帕金森病有关。在这里，我们使用 siRNA 介导的人 SH-SY5Y 细胞和 NAPE-PLD 小鼠中的 NAPE-PLD 沉默来确定 NAPEs 是否影响 LRRK2 的膜结合，LRRK2 是一种多功能蛋白激酶，在散发性帕金森病患者中经常发生突变。NAPE-PLD 的缺失导致未代谢的 NAPEs 大量积累，这伴随着 LRRK2 从膜到细胞质的转移以及总 LRRK2 含量的减少。相反，完整的 SH-SY5Y 细胞暴露于细菌 PLD 会降低 NAPE 水平并增强 LRRK2 与膜的结合。结果表明，NAPE-PLD 活性可能通过调节膜 NAPE 水平来控制 LRRK2 的定位。
