Na+/K+-ATP酶(NKA)的功能障碍已在各种神经退行性疾病中被证明。然而,NKAα1在帕金森病(PD)中的具体作用尚不完全清楚。在这次调查中,我们利用NKAα1单倍体功能不全(NKAα1/-)小鼠来探讨NKAα1对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的多巴胺能(DA)神经变性的影响。我们的发现表明,与暴露于MPTP的对照组相比,NKAα1/-小鼠表现出DA神经元的高度丧失和更明显的运动功能障碍。有趣的是,这种现象与体内和体外铁凋亡的激活和线粒体自噬的受损同时发生。为了研究NKAα1在PD中的作用和潜在机制,我们用了DR-Ab,靶向NKAα亚基的DR区的抗体。我们的研究表明,DR-Ab的施用有效地恢复了NKAa1的膜丰度,从而减轻了MPTP诱导的DA神经元丢失并随后改善了行为缺陷。机械上,DR-Ab增强了表面NKAα1/SLC7A11复合物的形成,抑制SLC7A11依赖性铁性凋亡。此外,DR-Ab破坏了NKAα1和Parkin之间的胞浆相互作用,促进Parkin向线粒体的易位并增强线粒体自噬的过程。总之,本研究确立了NKAα1作为铁凋亡和线粒体自噬的关键调节因子,确定其DR区作为PD的有希望的治疗靶标。
Dysfunction of the Na+/K+-ATPase (NKA) has been documented in various neurodegenerative diseases, yet the specific role of NKAα1 in Parkinson\'s disease (PD) remains incompletely understood. In this investigation, we utilized NKAα1
haploinsufficiency (NKAα1+/-) mice to probe the influence of NKAα1 on dopaminergic (DA) neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our findings reveal that NKAα1+/- mice displayed a heightened loss of DA neurons and more pronounced motor dysfunction compared to the control group when exposed to MPTP. Intriguingly, this phenomenon coincided with the activation of ferroptosis and impaired mitophagy both in vivo and in vitro. To scrutinize the role and underlying mechanism of NKAα1 in PD, we employed DR-Ab, an antibody targeting the DR-region of the NKA α subunit. Our study demonstrates that the administration of DR-Ab effectively reinstated the membrane abundance of NKAα1, thereby mitigating MPTP-induced DA neuron loss and subsequent improvement in behavioral deficit. Mechanistically, DR-Ab heightened the formation of the surface NKAα1/SLC7A11 complex, inhibiting SLC7A11-dependent ferroptosis. Moreover, DR-Ab disrupted the cytosolic interaction between NKAα1 and Parkin, facilitating the translocation of Parkin to mitochondria and enhancing the process of mitophagy. In conclusion, this study establishes NKAα1 as a key regulator of ferroptosis and mitophagy, identifying its DR-region as a promising therapeutic target for PD.