Hormos Salimi Dafsari, Diego Martinelli, Afshin Saffari, Darius Ebrahimi-Fakhari, Manolis Fanto, Carlo Dionisi-Vici, Heinz Jungbluth
{"title":"自噬疾病的最新进展。","authors":"Hormos Salimi Dafsari, Diego Martinelli, Afshin Saffari, Darius Ebrahimi-Fakhari, Manolis Fanto, Carlo Dionisi-Vici, Heinz Jungbluth","doi":"10.1002/jimd.12798","DOIUrl":null,"url":null,"abstract":"<p><p>Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post-mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common \"clinical signature\" including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of EPG5-related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy-associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico-pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"An update on autophagy disorders.\",\"authors\":\"Hormos Salimi Dafsari, Diego Martinelli, Afshin Saffari, Darius Ebrahimi-Fakhari, Manolis Fanto, Carlo Dionisi-Vici, Heinz Jungbluth\",\"doi\":\"10.1002/jimd.12798\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post-mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common \\\"clinical signature\\\" including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of EPG5-related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy-associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico-pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.</p>\",\"PeriodicalId\":16281,\"journal\":{\"name\":\"Journal of Inherited Metabolic Disease\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-10-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Inherited Metabolic Disease\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/jimd.12798\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Inherited Metabolic Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/jimd.12798","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
引用次数: 0
摘要
大自噬是一种高度保守的细胞途径,用于降解和回收有缺陷的货物,包括蛋白质、细胞器和大分子复合物。由于自噬与有丝分裂后组织的细胞稳态特别相关,由关键自噬基因的单基因缺陷导致的先天性自噬紊乱具有共同的 "临床特征",包括神经发育、神经退行性和神经肌肉特征,以及眼睛、皮肤、心脏、骨骼、免疫细胞和其他器官系统的不同异常,具体取决于缺陷蛋白的表达模式和特定功能。自 EPG5 相关的 Vici 综合征是自噬先天性疾病的典范,自从该综合征的临床和遗传问题得到解决后,大规模平行测序技术的广泛应用导致越来越多的自噬相关疾病基因被鉴定出来,这些基因编码自噬核心机制的成员以及相关蛋白。最近发现的将选择性自噬、囊泡运输和其他途径联系起来的单基因疾病进一步扩大了自噬先天性疾病的分子和表型谱,使之成为一种临床疾病谱。此外,基础研究的重大进展也加深了人们对潜在病理生理学的了解,为治疗方法的开发奠定了基础。在此,我们将回顾:(i) 自噬与其他细胞内转运途径的关系;(ii) 主要的自噬先天性疾病及其典型的临床病理特征;(iii) 基于现有证据推荐的自噬单基因疾病的初级健康监测。我们还进一步讨论了最近发现的分子机制,这些机制为目前了解自噬在健康和疾病中的作用提供了信息,并对未来的治疗方法提出了展望。
Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post-mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common "clinical signature" including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of EPG5-related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy-associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico-pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.
期刊介绍:
The Journal of Inherited Metabolic Disease (JIMD) is the official journal of the Society for the Study of Inborn Errors of Metabolism (SSIEM). By enhancing communication between workers in the field throughout the world, the JIMD aims to improve the management and understanding of inherited metabolic disorders. It publishes results of original research and new or important observations pertaining to any aspect of inherited metabolic disease in humans and higher animals. This includes clinical (medical, dental and veterinary), biochemical, genetic (including cytogenetic, molecular and population genetic), experimental (including cell biological), methodological, theoretical, epidemiological, ethical and counselling aspects. The JIMD also reviews important new developments or controversial issues relating to metabolic disorders and publishes reviews and short reports arising from the Society''s annual symposia. A distinction is made between peer-reviewed scientific material that is selected because of its significance for other professionals in the field and non-peer- reviewed material that aims to be important, controversial, interesting or entertaining (“Extras”).