Targeting selective autophagy in CNS disorders by small-molecule compounds

IF 12 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Yanrong Zheng , Zhuchen Zhou , Mengting Liu, Zhong Chen
{"title":"Targeting selective autophagy in CNS disorders by small-molecule compounds","authors":"Yanrong Zheng ,&nbsp;Zhuchen Zhou ,&nbsp;Mengting Liu,&nbsp;Zhong Chen","doi":"10.1016/j.pharmthera.2024.108729","DOIUrl":null,"url":null,"abstract":"<div><div>Autophagy functions as the primary cellular mechanism for clearing unwanted intracellular contents. Emerging evidence suggests that the selective elimination of intracellular organelles through autophagy, compared to the increased bulk autophagic flux, is crucial for the pathological progression of central nervous system (CNS) disorders. Notably, autophagic removal of mitochondria, known as mitophagy, is well-understood in an unhealthy brain. Accumulated data indicate that selective autophagy of other substrates, including protein aggregates, liposomes, and endoplasmic reticulum, plays distinctive roles in various pathological stages. Despite variations in substrates, the molecular mechanisms governing selective autophagy can be broadly categorized into two types: ubiquitin-dependent and -independent pathways, both of which can be subjected to regulation by small-molecule compounds. Notably, natural products provide the remarkable possibility for future structural optimization to regulate the highly selective autophagic clearance of diverse substrates. In this context, we emphasize the selectivity of autophagy in regulating CNS disorders and provide an overview of chemical compounds capable of modulating selective autophagy in these disorders, along with the underlying mechanisms. Further exploration of the functions of these compounds will in turn advance our understanding of autophagic contributions to brain disorders and illuminate precise therapeutic strategies for these diseases.</div></div>","PeriodicalId":402,"journal":{"name":"Pharmacology & Therapeutics","volume":"263 ","pages":"Article 108729"},"PeriodicalIF":12.0000,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacology & Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0163725824001499","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

Abstract

Autophagy functions as the primary cellular mechanism for clearing unwanted intracellular contents. Emerging evidence suggests that the selective elimination of intracellular organelles through autophagy, compared to the increased bulk autophagic flux, is crucial for the pathological progression of central nervous system (CNS) disorders. Notably, autophagic removal of mitochondria, known as mitophagy, is well-understood in an unhealthy brain. Accumulated data indicate that selective autophagy of other substrates, including protein aggregates, liposomes, and endoplasmic reticulum, plays distinctive roles in various pathological stages. Despite variations in substrates, the molecular mechanisms governing selective autophagy can be broadly categorized into two types: ubiquitin-dependent and -independent pathways, both of which can be subjected to regulation by small-molecule compounds. Notably, natural products provide the remarkable possibility for future structural optimization to regulate the highly selective autophagic clearance of diverse substrates. In this context, we emphasize the selectivity of autophagy in regulating CNS disorders and provide an overview of chemical compounds capable of modulating selective autophagy in these disorders, along with the underlying mechanisms. Further exploration of the functions of these compounds will in turn advance our understanding of autophagic contributions to brain disorders and illuminate precise therapeutic strategies for these diseases.
用小分子化合物靶向中枢神经系统疾病中的选择性自噬。
自噬是清除细胞内无用内容物的主要细胞机制。新的证据表明,与自噬通量的增加相比,通过自噬选择性地清除细胞内细胞器对中枢神经系统(CNS)疾病的病理发展至关重要。值得注意的是,在不健康的大脑中,线粒体的自噬清除(即线粒体吞噬)已被广泛了解。积累的数据表明,选择性自噬其他底物,包括蛋白质聚集体、脂质体和内质网,在不同的病理阶段发挥着不同的作用。尽管底物各不相同,但支配选择性自噬的分子机制可大致分为两类:泛素依赖性途径和非依赖性途径,这两种途径都可受到小分子化合物的调控。值得注意的是,天然产物为未来结构优化提供了非凡的可能性,以调节对不同底物的高度选择性自噬清除。在此背景下,我们强调自噬在调节中枢神经系统疾病中的选择性,并概述了能够调节这些疾病中选择性自噬的化合物及其内在机制。对这些化合物功能的进一步探索将反过来促进我们对自噬对脑部疾病贡献的理解,并为这些疾病的精确治疗策略提供启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
23.00
自引率
0.70%
发文量
222
审稿时长
90 days
期刊介绍: Pharmacology & Therapeutics, in its 20th year, delivers lucid, critical, and authoritative reviews on current pharmacological topics.Articles, commissioned by the editor, follow specific author instructions.This journal maintains its scientific excellence and ranks among the top 10 most cited journals in pharmacology.
×
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