Fanning Saranna, Cirka Haley, Thies Jennifer L, Jeong Jooyoung, Niemi Sarah M, Yoon Joon, Ho Gary P H, Pacheco Julian A, Dettmer Ulf, Liu Lei, Clish Clary B, Hodgetts Kevin J, Hutchinson John N, Muratore Christina R, Caldwell Guy A, Caldwell Kim A, Selkoe Dennis
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA.
NPJ Parkinsons Dis. 2022 Jun 9;8(1):74. doi: 10.1038/s41531-022-00335-6.
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）的疾病修饰治疗存在巨大的未满足医疗需求。尽管导致PD的蛋白质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稳态进行治疗仍处于起步阶段。我们确定了与PD相关的靶点硬脂酰辅酶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作为候选靶点。降低人神经细胞中的LIPE可减少αS包涵体。患者αS三倍体与校正神经元相比，pSer129和不溶性αS增加，αS四聚体：单体比率降低。LIPE抑制可挽救所有这些情况以及异常的未折叠蛋白反应。LIPE抑制剂可降低pSer129并恢复表达αS E46K的人神经元中的四聚体：单体平衡。体内LIPE减少可减轻秀丽隐杆线虫中αS诱导的多巴胺能神经变性。事实证明，共同调节FA合成和降解在挽救PD表型方面具有累加作用，这表明共同靶向是一种治疗策略。
