Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein
Intracellular delivery of Parkin rescues neurons from accumulation of damaged mitochondria and pathological α-synuclein
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DOI：
10.1126/sciadv.aba1193
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发表时间：
2020-04-01
期刊：
影响因子：
13.6
通讯作者：
Jo, Daewoong
中科院分区：
文献类型：
--
作者：
Chung, Eunna;Choi, Youngsil;Jo, Daewoong
帕金森病（PD）是一种进行性神经退行性疾病，以线粒体功能障碍、路易体形成和多巴胺能神经元丧失为特征。Parkin是一种E3泛素连接酶，被认为通过去除受损的线粒体和抑制α -突触核蛋白和其他蛋白质聚集体的积累来抑制PD的进展。本研究描述了一种基于蛋白质的PD治疗方法，该方法是通过开发一种具有增强溶解度和优化细胞内递送的细胞渗透性Parkin蛋白（iCP-Parkin）来实现的。iCP-Parkin通过促进线粒体自噬和线粒体恢复受损的线粒体！α -突触核蛋白在细胞和动物中的生物发生和抑制毒性积累。最后，iCP-Parkin预防和逆转线粒体中毒或α -突触核蛋白表达增强引起的酪氨酸羟化酶和多巴胺表达下降，并改善运动功能。这些结果指出了PD病理生理学中常见的、治疗上可处理的特征，并表明PD的运动缺陷可能被逆转，从而为运动症状出现后的治疗干预提供了机会。
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction, Lewy body formation, and loss of dopaminergic neurons. Parkin, an E3 ubiquitin ligase, is thought to inhibit PD progression by removing damaged mitochondria and suppressing the accumulation of alpha-synuclein and other protein aggregates. The present study describes a protein-based therapy for PD enabled by the development of a cell-permeable Parkin protein (iCP-Parkin) with enhanced solubility and optimized intracellular delivery. iCP-Parkin recovered damaged mitochondria by promoting mitophagy and mitochondria! biogenesis and suppressed toxic accumulations of alpha-synuclein in cells and animals. Last, iCP-Parkin prevented and reversed declines in tyrosine hydroxylase and dopamine expression concomitant with improved motor function induced by mitochondrial poisons or enforced alpha-synuclein expression. These results point to common, therapeutically tractable features in PD pathophysiology, and suggest that motor deficits in PD may be reversed, thus providing opportunities for therapeutic intervention after the onset of motor symptoms.