Enhancement of lysosome biogenesis as a potential therapeutic approach for neurodegenerative diseases

作     者：Wenlong Xue Jie Zhang Yang Li Wenlong Xue;Jie Zhang;Yang Li

作者机构：Department of PharmacologyState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain ScienceKey Laboratory of Metabolism and Molecular MedicineMinistry of EducationSchool of Basic Medical ScienceFudan UniversityShanghaiChina 

出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)

年 卷 期：2023年第18卷第11期

页      面：2370-2376页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100204[医学-神经病学] 10[医学] 

基　　金：STI2030-Major Projects,No.2022ZD0213000 the National Natural Science Foundation of China,Nos.92057103 and 31872820 Shanghai Basic Research Program,No.18ZR1 404000 State Key Laboratory of Drug Research,No.SIMM2004KF-09 (all to YL)。 

主　　题：Alzheimer’s disease degradation lysosome biogenesis LYsosome-Enhancing Compounds neurodegenerative diseases post-translational modifications protein aggregates transcription factor EB 

摘      要：Millions of people are suffering from Alzheimer’s disease globally,but there is still no effective treatment for this neurodegenerative disease.Thus,novel therapeutic approaches for Alzheimer’s disease are needed,which requires further evaluation of the regulato ry mechanisms of protein aggregate degradation.Lysosomes are crucial degradative organelles that maintain cellular homeostasis.Transcription factor EB-mediated lysosome biogenesis enhances autolysosomedependent degradation,which subsequently alleviates neurodege nerative diseases,including Alzheimer’s disease,Parkinson’s disease,and Huntington’s disease.In this review,we start by describing the key features of lysosomes,including their roles in nutrient sensing and degradation,and their functional impairments in different neurodegenerative diseases.We also explain the mechanisms—especially the post-translational modifications—which impact transcription factor EB and regulate lysosome biogenesis.Next,we discuss strategies for promoting the degradation of toxic protein aggregates.We describe Proteolysis-Ta rgeting Chimera and related technologies for the targeted degradation of specific proteins.We also introduce a group of LYsosome-Enhancing Compounds,which promote transcription factor EB-mediated lysosome biogenesis and improve learning,memory,and cognitive function in APP-PSEN1 mice.In summary,this review highlights the key aspects of lysosome biology,the mechanisms of transcription factor EB activation and lysosome biogenesis,and the promising strategies which are emerging to alleviate the pathogenesis of neurodegenerative diseases.