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ATG7介导自噬缺陷对人体发育造成的后果
Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans


Jack J. Collier ... 其他 • 2021.06.24
相关阅读
• 自噬在人类疾病中的作用

自噬蛋白ATG7突变导致神经发育障碍和肌肉骨骼异常

 

秦环龙†*,吴伟军†,胡荣贵‡*

†同济大学附属第十人民医院;‡中国科学院分子细胞科学卓越创新中心

*并列通讯作者

 

2016年诺贝尔生理学或医学奖由日本科学家大隅良典(Yoshinori Ohsumi)获得,其贡献是发现了细胞自噬(autophagy)机制。在特定环境下,自噬作为机体细胞维持内稳态的重要机制,调控细胞内蛋白质和细胞器在溶酶体中降解,以及回收利用。从20世纪50年代溶酶体首次被de Duve发现,到90年代自噬相关基因(autophagy-related genes,ATG)逐一被阐明,我们对于自噬的理解也从单一的宏观现象观察跨越到了基因水平的探讨。在过去10年中,自噬研究又发生了质的飞跃,其已经从单纯的分子机制研究延伸到了多种威胁人类健康的疾病领域,如癌症、病原微生物感染及老年痴呆等。

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摘要


背景

自噬是哺乳动物细胞内的主要降解途径。对小鼠的自噬相关核心基因(ATG)实施全身消融会导致胚胎死亡或围产期死亡,条件模型显示神经变性。自噬受损与一系列复杂的人类疾病相关,但先天性自噬障碍罕见。

 

方法

我们对5个家族进行了遗传、临床和神经影像学分析。使用来自患者的成纤维细胞、骨骼肌活检标本、小鼠胚胎成纤维细胞和酵母进行了机制研究。

 

结果

我们发现了人类ATG7的有害隐性变异,ATG7是自噬相关核心基因,编码经典降解性自噬必需的蛋白。12例患者来自有不同ATG7变异的5个家族,他们患累及脑、肌肉和内分泌系统的复杂神经发育障碍。患者有小脑、胼胝体异常,以及不同程度的面部畸形。这些患者在ATG7蛋白减少或缺失导致自噬通量受损的情况下存活。虽然自噬隔离(autophagic sequestration)明显减少,但我们可以很容易地在ATG7丧失的成纤维细胞和骨骼肌中发现基础自噬的证据。与再引入野生型ATG7相比,采用有害ATG7变异补充不同模型系统后产生的自噬功能较差或缺失。

 

结论

我们发现了数例在ATG7(自噬的必需效应酶,无已知的功能类似物)严重缺失或完全缺失的情况下存活的神经发育障碍患者(由威康线粒体研究中心[Wellcome Centre for Mitochondrial Research]等资助)。





作者信息

Jack J. Collier, Ph.D., Claire Guissart, Pharm.D., Monika Oláhová, Ph.D., Souphatta Sasorith, Ph.D., Florence Piron-Prunier, M.Sc., Fumi Suomi, Ph.D., David Zhang, M.Sc., Nuria Martinez-Lopez, Ph.D., Nicolas Leboucq, M.D., Angela Bahr, Ph.D., Silvia Azzarello-Burri, M.D., Selina Reich, M.Sc., Ludger Schöls, M.D., Tuomo M. Polvikoski, Ph.D., Pierre Meyer, M.D., Lise Larrieu, M.Sc., Andrew M. Schaefer, M.R.C.P., Hessa S. Alsaif, B.Sc., Suad Alyamani, M.D., Stephan Zuchner, Ph.D., Inês A. Barbosa, Ph.D., Charu Deshpande, F.R.C.P., Angela Pyle, Ph.D., Anita Rauch, M.D., Matthis Synofzik, M.D., Fowzan S. Alkuraya, M.D., François Rivier, M.D., Mina Ryten, Ph.D., Robert McFarland, Ph.D., Agnès Delahodde, Ph.D., Thomas G. McWilliams, Ph.D., Michel Koenig, M.D., and Robert W. Taylor, Ph.D.
From the Wellcome Centre for Mitochondrial Research, (J.J.C., M.O., N.M.-L., A.M.S., A.P., R.M., R.W.T.), the Translational and Clinical Research Institute (J.J.C, M.O., T.M.P., A.M.S., A.P., R.M., R.W.T.), and the NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children (A.M.S., R.M., R.W.T.), Newcastle University, Newcastle Upon Tyne, and the Institute of Child Health, Department of Molecular Neuroscience, University College London Institute of Neurology (D.Z., M.R.), the Division of Genetics and Molecular Medicine, Guy’s Hospital, King’s College London School of Medicine (I.A.B.), and the Clinical Genetics Unit, Guy’s and St. Thomas’ NHS Foundation Trust (C.D.), London — all in the United Kingdom; Institut Universitaire de Recherche Clinique and Laboratoire de Génétique Moléculaire, University of Montpellier and Centre Hospitalier Universitaire (CHU) de Montpellier (C.G., S.S., L.L., M.K.), Departments of Neuroradiology (N.L.) and Pediatric Neurology (P.M., F.R.) and Reference Center for Neuromuscular Diseases Atlantic–Occitania–Caribbean (AOC) (P.M., F.R.), CHU de Montpellier, and Laboratoire de Physiologie et Médecine Expérimentale du Cœur et des Muscles (PhyMedExp), INSERM, CNRS, University of Montpellier (P.M., F.R.), Montpellier, and the Institute for Integrative Biology of the Cell (I2BC), Université Paris–Saclay, Alternative Energies and Atomic Energy Commission (CEA), CNRS Gif-sur-Yvette (F.P.-P., A.D.) — all in France; the Translational Stem Cell Biology and Metabolism Program, Research Programs Unit, and the Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki (F.S., T.G.M.); Radiation Oncology, Albert Einstein College of Medicine, New York (N.M.-L.); the Institute of Medical Genetics, University of Zurich, Zurich, Switzerland (A.B., S.A.-B., A.R.); Hertie Institute for Clinical Brain Research and Center of Neurology, and the German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany (S.R., L.S., M.S.); the Departments of Genetics (H.S.A., F.S.A.) and Neuroscience (S.A.), King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; and the Dr. John T. Macdonald Foundation, Department of Human Genetics, and John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami (S.Z.). Address reprint requests to Dr. Taylor at the Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Framlington Pl., Newcastle Upon Tyne, NE2 4HH, United Kingdom, or at robert.taylor@ncl.ac.uk. Agnès Delahodde is deceased.

 

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