抗 Na/K-ATPase 免疫疗法通过激活 Na/K-ATPaseα1 依赖性自噬改善α-突触核蛋白病理。

Anti-Na/K-ATPase immunotherapy ameliorates α-synuclein pathology through activation of Na/K-ATPase α1-dependent autophagy.

机构信息

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen 518055, PR China.

出版信息

Sci Adv. 2021 Jan 27;7(5). doi: 10.1126/sciadv.abc5062. Print 2021 Jan.

DOI:10.1126/sciadv.abc5062

PMID:33571110

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7840131/

Abstract

Na/K-ATPase (NKA) plays important roles in maintaining cellular homeostasis. Conversely, reduced NKA activity has been reported in aging and neurodegenerative diseases. However, little is known about the function of NKA in the pathogenesis of Parkinson's disease (PD). Here, we report that reduction of NKA activity in NKAα1 mice aggravates α-synuclein-induced pathology, including a reduction in tyrosine hydroxylase (TH) and deficits in behavioral tests for memory, learning, and motor function. To reverse this effect, we generated an NKA-stabilizing monoclonal antibody, DR5-12D, against the DR region (DVEDSYGQQWTYEQR) of the NKAα1 subunit. We demonstrate that DR5-12D can ameliorate α-synuclein-induced TH loss and behavioral deficits by accelerating α-synuclein degradation in neurons. The underlying mechanism for the beneficial effects of DR5-12D involves activation of NKAα1-dependent autophagy via increased AMPK/mTOR/ULK1 pathway signaling. Cumulatively, this work demonstrates that NKA activity is neuroprotective and that pharmacological activation of this pathway represents a new therapeutic strategy for PD.

摘要

钠钾 ATP 酶（NKA）在维持细胞内稳态方面发挥着重要作用。相反，在衰老和神经退行性疾病中，NKA 的活性已经降低。然而，关于 NKA 在帕金森病（PD）发病机制中的作用知之甚少。在这里，我们报告说，NKAα1 小鼠中 NKA 活性的降低会加重α-突触核蛋白诱导的病理，包括酪氨酸羟化酶（TH）的减少以及记忆、学习和运动功能的行为测试缺陷。为了逆转这种效应，我们生成了一种针对 NKAα1 亚基的 DR 区（DVEDSYGQQWTYEQR）的 NKA 稳定单克隆抗体 DR5-12D。我们证明，DR5-12D 可以通过加速神经元中α-突触核蛋白的降解来改善α-突触核蛋白诱导的 TH 丧失和行为缺陷。DR5-12D 产生有益效果的潜在机制涉及通过增加 AMPK/mTOR/ULK1 通路信号转导来激活 NKAα1 依赖性自噬。总而言之，这项工作表明 NKA 活性具有神经保护作用，而该途径的药理学激活代表了 PD 的一种新的治疗策略。