Synucleinopathy (Parkinson’s disease (PD); Lewy body dementia) disease-modifying treatments represent a huge unmet medical need. Although the PD-causing protein α-synuclein (αS) interacts with lipids and fatty acids (FA) physiologically and pathologically, targeting FA homeostasis for therapeutics is in its infancy. We identified the PD-relevant target stearoyl-coA desaturase: inhibiting monounsaturated FA synthesis reversed PD phenotypes. However, lipid degradation also generates FA pools. Here, we identify the rate-limiting lipase enzyme, LIPE, as a candidate target. Decreasing LIPE in human neural cells reduced αS inclusions. Patient αS triplication vs. corrected neurons had increased pSer129 and insoluble αS and decreased αS tetramer:monomer ratios. LIPE inhibition rescued all these and the abnormal unfolded protein response. LIPE inhibitors decreased pSer129 and restored tetramer:monomer equilibrium in αS E46K-expressing human neurons. LIPE reduction in vivo alleviated αS-induced dopaminergic neurodegeneration in Caenorhabditis elegans. Co-regulating FA synthesis and degradation proved additive in rescuing PD phenotypes, signifying co-targeting as a therapeutic strategy.

突触核蛋白病（帕金森病 (PD)；路易体痴呆）疾病缓解治疗代表了巨大的未满足的医疗需求。尽管引起 PD 的蛋白 α-突触核蛋白 (αS) 在生理和病理上与脂质和脂肪酸 (FA) 相互作用，但针对 FA 稳态的治疗仍处于起步阶段。我们确定了与 PD 相关的目标硬脂酰辅酶 A 去饱和酶：抑制单不饱和 FA 合成可逆转 PD 表型。然而，脂质降解也会产生 FA 库。在这里，我们确定限速脂肪酶 LIPE 作为候选靶标。人类神经细胞中 LIPE 的减少会减少 αS 内含物。与校正的神经元相比，患者 αS 三倍体增加了 pSer129 和不溶性 αS，并降低了 αS 四聚体：单体比率。 LIPE 抑制挽救了所有这些以及异常的未折叠蛋白反应。 LIPE 抑制剂可降低表达 αS E46K 的人类神经元中的 pSer129 并恢复四聚体：单体平衡。 LIPE 体内减少减轻了 αS 诱导的秀丽隐杆线虫多巴胺能神经变性。事实证明，共同调节 FA 合成和降解对于挽救 PD 表型具有附加作用，这表明共同靶向是一种治疗策略。