溶酶体脂质翻转酶ATP10B的缺失导致进行性多巴胺能神经变性和帕金森运动障碍。

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY
María Sanchiz-Calvo, Elena Coccia, Christopher Cawthorne, Gustavo Morrone Parfitt, Teresa Torre-Muruzabal, George Tsafaras, Koen Van Laere, Diego Cabezudo, Ana Cascalho, Chris Van den Haute, Peter Vangheluwe, Joel Blanchard, Eduard Bentea, Veerle Baekelandt
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引用次数: 0

摘要

ATP10B是一种位于内体和溶酶体晚期的跨膜脂质翻转酶,通过将该过程与ATP水解偶联,促进葡萄糖神经酰胺和磷脂酰胆碱的输出。最近,在帕金森病患者中发现了ATP10B基因的功能丧失突变,这表明ATP10B是一个候选的遗传风险因素。先前的研究表明,在人类细胞系和初级皮层神经元中,ATP10B基因敲低会损害溶酶体的功能。为了研究ATP10B在帕金森病神经病理学中的作用,特别是在黑质纹状体多巴胺能系统中的作用,我们利用病毒载体技术诱导大鼠黑质致密部神经元特异性敲低ATP10B。此外,利用ATP10B敲除的人诱导多能干细胞克隆获得的中脑神经元培养物,在更具转译性的模型中研究了ATP10B缺失对多巴胺能神经元的影响。Atp10b敲低大鼠脑诱导帕金森运动缺陷,纵向纹状体多巴胺转运体18F-FE-PE2I PET成像显示其结合电位进行性降低。注射一年后进行的免疫组织化学分析证实纹状体中多巴胺能末梢的丧失,以及黑质致密部多巴胺能神经元的丧失。研究了LAMP1、LAMP2a、组织蛋白酶B和葡萄糖脑苷酶在多巴胺能神经元中的表达。溶酶体数量的减少和溶酶体体积的增加在其中一种敲低结构中观察到更一致。在ATP10B敲除的人诱导多能干细胞克隆的中脑神经元培养物中也观察到多巴胺能神经元对ATP10B功能丧失的易感性,th阳性神经元显著减少。综上所述,我们的研究结果表明,ATP10B的消耗对体内和体外多巴胺能神经元的活力都有不利影响。此外,Atp10b基因敲低的大鼠表现出与帕金森病患者相似的运动损伤,证明了对黑质纹状体通路功能的更广泛影响。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Loss of the lysosomal lipid flippase ATP10B leads to progressive dopaminergic neurodegeneration and parkinsonian motor deficits.

ATP10B, a transmembrane lipid flippase located in late endosomes and lysosomes, facilitates the export of glucosylceramide and phosphatidylcholine by coupling this process to ATP hydrolysis. Recently, loss-of-function mutations in the ATP10B gene have been identified in Parkinson's disease patients, pointing to ATP10B as a candidate genetic risk factor. Previous studies have shown compromised lysosomal functionality upon ATP10B knockdown in human cell lines and primary cortical neurons. To investigate the role of ATP10B in Parkinson's disease neuropathology, specifically in the nigrostriatal dopaminergic system, we induced ATP10B knockdown specifically in substantia nigra pars compacta neurons of rats using viral vector technology. Additionally, midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones were used to study the impact of ATP10B loss in dopaminergic neurons in a more translational model. Atp10b knockdown in rat brain induced parkinsonian motor deficits, and longitudinal striatal dopamine transporter 18F-FE-PE2I PET imaging revealed a progressive decrease in binding potential. Immunohistochemical analysis conducted one year post-injection confirmed the loss of dopaminergic terminals in the striatum, alongside a loss of dopaminergic neurons in the substantia nigra pars compacta. The expression of LAMP1, LAMP2a, cathepsin B and glucocerebrosidase was studied in dopaminergic neurons. A decrease in lysosomal numbers and an increase in lysosomal volume were observed more consistently in one of the knockdown constructs. The vulnerability of dopaminergic neurons to ATP10B loss-of-function was also observed in midbrain neuronal cultures derived from ATP10B knock-out human induced pluripotent stem cells clones, which showed a significant reduction in TH-positive neurons. Taken together, our findings demonstrate that ATP10B depletion detrimentally impacts the viability of dopaminergic neurons both in vivo and in vitro. Moreover, a broader impact on the functionality of the nigrostriatal pathway was evidenced as rats with Atp10b knockdown exhibited motor impairments similar to those observed in Parkinson's disease patients.

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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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