<br>ALCAT1 的心磷脂重塑将线粒体功能障碍与帕金森病联系起来。,Aging Cell

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ALCAT1 的心磷脂重塑将线粒体功能障碍与帕金森病联系起来。
Aging Cell ( IF 8.0 ) Pub Date : 2019-03-05 , DOI: 10.1111/acel.12941
Chengjie Song _{1,

2} , Jun Zhang ₃ , Shasha Qi ₄ , Zhen Liu ₁ , Xiaoyang Zhang ₁ , Yue Zheng ₁ , John-Paul Andersen ₂ , Weiping Zhang ₄ , Randy Strong ₂ , Paul Anthony Martinez ₂ , Nicolas Musi ₂ , Jia Nie ₂ , Yuguang Shi _{1,

2}

Affiliation

心磷脂 (CL) 是一种线粒体特征磷脂，是膜结构、呼吸、动力学和线粒体自噬所必需的。活性氧对 CL 的氧化损伤与帕金森病 (PD) 的发病机制有关，但根本原因仍然难以捉摸。这项工作在 1-甲基-4-苯基-1,2,4,6-四氢吡啶 (MPTP) 诱导的 PD 小鼠模型中研究了 ALCAT1 的作用，ALCAT1 是一种酰基转移酶，可催化 CL 在各种衰老相关疾病中的病理重塑。）。我们发现 MPTP 治疗会导致中脑氧化应激、线粒体 DNA 突变和线粒体功能障碍。相比之下， ALCAT1基因的消除或 ALCAT1 的药理学抑制可防止 MPTP 诱导的神经毒性、细胞凋亡和运动缺陷。 ALCAT1 缺乏还通过调节 DRP1 易位到线粒体来减轻线粒体功能障碍。此外，对 ALCAT1 的药理抑制可促进 Parkin 募集至功能失调的线粒体，从而显着改善线粒体自噬。最后，MPTP 和 α-突触核蛋白病（PD 的一个关键标志）上调了 ALCAT1 的表达，而 ALCAT1 缺乏则阻止了 α-突触核蛋白寡聚化和 S-129 磷酸化，这表明 ALCAT1 在 PD 小鼠模型的病因学中发挥着关键作用。总之，这些发现将 ALCAT1 确定为治疗 PD 的新药物靶点。

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Cardiolipin remodeling by ALCAT1 links mitochondrial dysfunction to Parkinson's diseases.

Cardiolipin (CL) is a mitochondrial signature phospholipid that is required for membrane structure, respiration, dynamics, and mitophagy. Oxidative damage of CL by reactive oxygen species is implicated in the pathogenesis of Parkinson's disease (PD), but the underlying cause remains elusive. This work investigated the role of ALCAT1, an acyltransferase that catalyzes pathological remodeling of CL in various aging‐related diseases, in a mouse model of PD induced by 1‐methyl‐4‐phenyl‐1,2,4,6‐tetrahydropyridine (MPTP). We show that MPTP treatment caused oxidative stress, mtDNA mutations, and mitochondrial dysfunction in the midbrain. In contrast, ablation of the ALCAT1 gene or pharmacological inhibition of ALCAT1 prevented MPTP‐induced neurotoxicity, apoptosis, and motor deficits. ALCAT1 deficiency also mitigated mitochondrial dysfunction by modulating DRP1 translocation to the mitochondria. Moreover, pharmacological inhibition of ALCAT1 significantly improved mitophagy by promoting the recruitment of Parkin to dysfunctional mitochondria. Finally, ALCAT1 expression was upregulated by MPTP and by α‐synucleinopathy, a key hallmark of PD, whereas ALCAT1 deficiency prevented α‐synuclein oligomerization and S‐129 phosphorylation, implicating a key role of ALCAT1 in the etiology of mouse models of PD. Together, these findings identify ALCAT1 as a novel drug target for the treatment of PD.

更新日期：2019-03-05

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