核α-突触核蛋白会加速细胞衰老和神经退行性变。

IF 5.2 2区 医学 Q1 GERIATRICS & GERONTOLOGY
Tingfu Du, Guoxiang Li, Qinglan Zong, Haiyu Luo, Yue Pan, Kaili Ma
{"title":"核α-突触核蛋白会加速细胞衰老和神经退行性变。","authors":"Tingfu Du, Guoxiang Li, Qinglan Zong, Haiyu Luo, Yue Pan, Kaili Ma","doi":"10.1186/s12979-024-00429-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The progression of Parkinson's disease (PD) is related to ageing. The accumulation of nuclear alpha-synuclein (α-syn) may accelerate the occurrence of neurodegenerative diseases, but its role in PD remains poorly understood.</p><p><strong>Methods: </strong>In the present study, α-syn expression was specifically targeted to the nucleus by constructing an adeno-associated virus (AAV) vector in which a nuclear localization sequence (NLS) was added to the α-syn coding sequence. Virus-mediated gene transfer, behavioural tests, RNA-Seq, immunohistochemistry, western blotting, and quantitative real-time PCR were then performed.</p><p><strong>Results: </strong>In vivo experiments using a mouse model showed that nuclear α-syn increased the severity of the PD-like phenotype, including the loss of dopaminergic neurons concomitant with motor impairment and the formation of α-syn inclusions. These nuclear inclusions contained α-syn species of high molecular weights and induced strong transcriptional dysregulation, especially induced high expression of p21 and senescence-associated secretory phenotype (SASP)-related genes. In addition, the transcriptional alterations induced by nuclear α-syn were associated with gliosis, inflammation, oxidative and DNA damage, and lysosomal dysfunction, and they eventually accelerated neuronal loss and neurodegeneration.</p><p><strong>Conclusions: </strong>Our results suggest that nuclear α-syn plays a crucial role in PD pathogenesis.</p>","PeriodicalId":51289,"journal":{"name":"Immunity & Ageing","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11242018/pdf/","citationCount":"0","resultStr":"{\"title\":\"Nuclear alpha-synuclein accelerates cell senescence and neurodegeneration.\",\"authors\":\"Tingfu Du, Guoxiang Li, Qinglan Zong, Haiyu Luo, Yue Pan, Kaili Ma\",\"doi\":\"10.1186/s12979-024-00429-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The progression of Parkinson's disease (PD) is related to ageing. The accumulation of nuclear alpha-synuclein (α-syn) may accelerate the occurrence of neurodegenerative diseases, but its role in PD remains poorly understood.</p><p><strong>Methods: </strong>In the present study, α-syn expression was specifically targeted to the nucleus by constructing an adeno-associated virus (AAV) vector in which a nuclear localization sequence (NLS) was added to the α-syn coding sequence. Virus-mediated gene transfer, behavioural tests, RNA-Seq, immunohistochemistry, western blotting, and quantitative real-time PCR were then performed.</p><p><strong>Results: </strong>In vivo experiments using a mouse model showed that nuclear α-syn increased the severity of the PD-like phenotype, including the loss of dopaminergic neurons concomitant with motor impairment and the formation of α-syn inclusions. These nuclear inclusions contained α-syn species of high molecular weights and induced strong transcriptional dysregulation, especially induced high expression of p21 and senescence-associated secretory phenotype (SASP)-related genes. In addition, the transcriptional alterations induced by nuclear α-syn were associated with gliosis, inflammation, oxidative and DNA damage, and lysosomal dysfunction, and they eventually accelerated neuronal loss and neurodegeneration.</p><p><strong>Conclusions: </strong>Our results suggest that nuclear α-syn plays a crucial role in PD pathogenesis.</p>\",\"PeriodicalId\":51289,\"journal\":{\"name\":\"Immunity & Ageing\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":5.2000,\"publicationDate\":\"2024-07-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11242018/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Immunity & Ageing\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s12979-024-00429-0\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GERIATRICS & GERONTOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunity & Ageing","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12979-024-00429-0","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

背景:帕金森病(PD)的进展与衰老有关。核α-突触核蛋白(α-syn)的积累可能会加速神经退行性疾病的发生,但其在帕金森病中的作用仍鲜为人知:本研究通过构建一种腺相关病毒(AAV)载体,在α-syn编码序列中加入核定位序列(NLS),将α-syn表达特异性靶向到细胞核。然后进行了病毒介导的基因转移、行为测试、RNA-Seq、免疫组织化学、Western 印迹和定量实时 PCR:结果:使用小鼠模型进行的体内实验表明,核α-syn增加了类帕金森病表型的严重性,包括多巴胺能神经元的丧失,同时伴有运动障碍和α-syn包涵体的形成。这些核内含物含有高分子量的α-syn物种,并诱导了强烈的转录失调,尤其是诱导了p21和衰老相关分泌表型(SASP)相关基因的高表达。此外,核α-syn诱导的转录改变还与胶质细胞病变、炎症、氧化和DNA损伤以及溶酶体功能障碍有关,它们最终加速了神经元丢失和神经退行性变:我们的研究结果表明,核α-syn在帕金森病发病机制中起着至关重要的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nuclear alpha-synuclein accelerates cell senescence and neurodegeneration.

Background: The progression of Parkinson's disease (PD) is related to ageing. The accumulation of nuclear alpha-synuclein (α-syn) may accelerate the occurrence of neurodegenerative diseases, but its role in PD remains poorly understood.

Methods: In the present study, α-syn expression was specifically targeted to the nucleus by constructing an adeno-associated virus (AAV) vector in which a nuclear localization sequence (NLS) was added to the α-syn coding sequence. Virus-mediated gene transfer, behavioural tests, RNA-Seq, immunohistochemistry, western blotting, and quantitative real-time PCR were then performed.

Results: In vivo experiments using a mouse model showed that nuclear α-syn increased the severity of the PD-like phenotype, including the loss of dopaminergic neurons concomitant with motor impairment and the formation of α-syn inclusions. These nuclear inclusions contained α-syn species of high molecular weights and induced strong transcriptional dysregulation, especially induced high expression of p21 and senescence-associated secretory phenotype (SASP)-related genes. In addition, the transcriptional alterations induced by nuclear α-syn were associated with gliosis, inflammation, oxidative and DNA damage, and lysosomal dysfunction, and they eventually accelerated neuronal loss and neurodegeneration.

Conclusions: Our results suggest that nuclear α-syn plays a crucial role in PD pathogenesis.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Immunity & Ageing
Immunity & Ageing GERIATRICS & GERONTOLOGY-IMMUNOLOGY
CiteScore
10.20
自引率
3.80%
发文量
55
期刊介绍: Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信