{"title":"神经退行性疾病中自噬-溶酶体功能障碍的机制","authors":"Ralph A. Nixon, David C. Rubinsztein","doi":"10.1038/s41580-024-00757-5","DOIUrl":null,"url":null,"abstract":"Autophagy is a lysosome-based degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and aggregate-prone proteins. Their postmitotic nature and extremely polarized morphologies make neurons particularly vulnerable to disruptions caused by autophagy–lysosomal defects, especially as the brain ages. Consequently, mutations in genes regulating autophagy and lysosomal functions cause a wide range of neurodegenerative diseases. Here, we review the role of autophagy and lysosomes in neurodegenerative diseases such as Alzheimer disease, Parkinson disease and frontotemporal dementia. We also consider the strong impact of cellular ageing on lysosomes and autophagy as a tipping point for the late-age emergence of related neurodegenerative disorders. Many of these diseases have primary defects in autophagy, for example affecting autophagosome formation, and in lysosomal functions, especially pH regulation and calcium homeostasis. We have aimed to provide an integrative framework for understanding the central importance of autophagic–lysosomal function in neuronal health and disease. The autophagy–lysosome pathway eliminates damaged organelles and aggregation-prone proteins, which is particularly important in neurons, where clearance of such substrates is restricted. Autophagy or lysosome deficiencies, often exacerbated by ageing, impact neuronal function and cause neurodegenerative diseases such as Alzheimer disease or Parkinson disease.","PeriodicalId":19051,"journal":{"name":"Nature Reviews Molecular Cell Biology","volume":null,"pages":null},"PeriodicalIF":81.3000,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases\",\"authors\":\"Ralph A. Nixon, David C. Rubinsztein\",\"doi\":\"10.1038/s41580-024-00757-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Autophagy is a lysosome-based degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and aggregate-prone proteins. Their postmitotic nature and extremely polarized morphologies make neurons particularly vulnerable to disruptions caused by autophagy–lysosomal defects, especially as the brain ages. Consequently, mutations in genes regulating autophagy and lysosomal functions cause a wide range of neurodegenerative diseases. Here, we review the role of autophagy and lysosomes in neurodegenerative diseases such as Alzheimer disease, Parkinson disease and frontotemporal dementia. We also consider the strong impact of cellular ageing on lysosomes and autophagy as a tipping point for the late-age emergence of related neurodegenerative disorders. Many of these diseases have primary defects in autophagy, for example affecting autophagosome formation, and in lysosomal functions, especially pH regulation and calcium homeostasis. We have aimed to provide an integrative framework for understanding the central importance of autophagic–lysosomal function in neuronal health and disease. The autophagy–lysosome pathway eliminates damaged organelles and aggregation-prone proteins, which is particularly important in neurons, where clearance of such substrates is restricted. Autophagy or lysosome deficiencies, often exacerbated by ageing, impact neuronal function and cause neurodegenerative diseases such as Alzheimer disease or Parkinson disease.\",\"PeriodicalId\":19051,\"journal\":{\"name\":\"Nature Reviews Molecular Cell Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":81.3000,\"publicationDate\":\"2024-08-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Reviews Molecular Cell Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://www.nature.com/articles/s41580-024-00757-5\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Reviews Molecular Cell Biology","FirstCategoryId":"99","ListUrlMain":"https://www.nature.com/articles/s41580-024-00757-5","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Mechanisms of autophagy–lysosome dysfunction in neurodegenerative diseases
Autophagy is a lysosome-based degradative process used to recycle obsolete cellular constituents and eliminate damaged organelles and aggregate-prone proteins. Their postmitotic nature and extremely polarized morphologies make neurons particularly vulnerable to disruptions caused by autophagy–lysosomal defects, especially as the brain ages. Consequently, mutations in genes regulating autophagy and lysosomal functions cause a wide range of neurodegenerative diseases. Here, we review the role of autophagy and lysosomes in neurodegenerative diseases such as Alzheimer disease, Parkinson disease and frontotemporal dementia. We also consider the strong impact of cellular ageing on lysosomes and autophagy as a tipping point for the late-age emergence of related neurodegenerative disorders. Many of these diseases have primary defects in autophagy, for example affecting autophagosome formation, and in lysosomal functions, especially pH regulation and calcium homeostasis. We have aimed to provide an integrative framework for understanding the central importance of autophagic–lysosomal function in neuronal health and disease. The autophagy–lysosome pathway eliminates damaged organelles and aggregation-prone proteins, which is particularly important in neurons, where clearance of such substrates is restricted. Autophagy or lysosome deficiencies, often exacerbated by ageing, impact neuronal function and cause neurodegenerative diseases such as Alzheimer disease or Parkinson disease.
期刊介绍:
Nature Reviews Molecular Cell Biology is a prestigious journal that aims to be the primary source of reviews and commentaries for the scientific communities it serves. The journal strives to publish articles that are authoritative, accessible, and enriched with easily understandable figures, tables, and other display items. The goal is to provide an unparalleled service to authors, referees, and readers, and the journal works diligently to maximize the usefulness and impact of each article. Nature Reviews Molecular Cell Biology publishes a variety of article types, including Reviews, Perspectives, Comments, and Research Highlights, all of which are relevant to molecular and cell biologists. The journal's broad scope ensures that the articles it publishes reach the widest possible audience.