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Inhibition of the dopamine transporter promotes lysosome biogenesis and ameliorates Alzheimer's disease-like symptoms in mice

文献类型：期刊论文

作者Yin, Limin4,5; Zhou, Jianhui2,3; Li, Tianyou4,5; Wang, Xinghua2; Xue, Wenlong4,5; Zhang, Jie4,5; Lin, Lingxi4,5; Wang, Ning4,5; Kang, Xinyi4,5; Zhou, Yu1,2,3
刊名ALZHEIMERS & DEMENTIA
出版日期2022-09-21
页码15
ISSN号1552-5260
关键词Alzheimer's disease CDK9 dopamine transporter lysosome biogenesis TFEB
DOI10.1002/alz.12776
通讯作者Li, Yang(oceanyangli@fudan.edu.cn)
英文摘要Introduction Lysosomes are degradative organelles that maintain cellular homeostasis and protein quality control. Transcription factor EB (TFEB)-mediated lysosome biogenesis enhances lysosome-dependent degradation and alleviates neurodegenerative diseases, but the mechanisms underlying TFEB regulation and modification are still poorly understood. Methods By screening novel small-molecule compounds, we identified a group of lysosome-enhancing compounds (LYECs) that promote TFEB activation and lysosome biogenesis. Results One of these compounds, LH2-051, significantly inhibited the function of the dopamine transporter (DAT) and subsequently promoted lysosome biogenesis. We uncovered cyclin-dependent kinase 9 (CDK9) as a novel regulator of DAT-mediated lysosome biogenesis and identified six novel CDK9-phosphorylated sites on TFEB. We observed that signal transduction by the DAT-CDK9-TFEB axis occurs on lysosomes. Finally, we found that LH2-051 enhanced the degradation of amyloid beta plaques and improved the memory of amyloid precursor protein (APP)/Presenilin 1 (PS1) mice. Discussion We identified the DAT-CDK9-TFEB signaling axis as a novel regulator of lysosome biogenesis. Our study sheds light on the mechanisms of protein quality control under pathophysiological conditions.
WOS关键词HYBRID APPROACH ; DEGRADATION ; DYSFUNCTION ; MECHANISMS ; AUTOPHAGY ; SHAFTS ; TFEB
资助项目Ministry of Science and Technology of the People's Republic of China[2022ZD0213000] ; National Natural Science Foundation of China[92057103] ; National Natural Science Foundation of China[31872820] ; National Natural Science Foundation of China[91953108] ; National Natural Science Foundation of China[82130105] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[82173656] ; Shanghai Basic Research Program[18ZR1404000] ; State Key Laboratory of Drug Research[SIMM2004KF-09] ; Lingang Laboratory[LG202103-01-03] ; Lingang Laboratory[LG2020103-01-05] ; Innovative Research Team of High-Level Local Universities in Shanghai ; Key Laboratory Programof the Education Commission of Shanghai Municipality[ZDSYS14005] ; China Postdoctoral Science Foundation[2020TQ0070]
WOS研究方向Neurosciences & Neurology
语种英语
出版者WILEY
WOS记录号WOS:000857966800001
源URL[http://119.78.100.183/handle/2S10ELR8/302458]  
专题新药研究国家重点实验室
通讯作者Li, Yang
作者单位1.Univ Chinese Acad Sci, Sch Pharm, Beijing, Peoples R China
2.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
4.Fudan Univ, MOE Frontiers Ctr Brain Sci, Key Lab Metab & Mol Med, Minist Educ,Sch Basic Med Sci, 138 Yi Xue Yuan Rd, Shanghai 200032, Peoples R China
5.Fudan Univ, State Key Lab Med Neurobiol, Sch Basic Med Sci, Dept Pharmacol,Minist Educ, 138 Yi Xue Yuan Rd, Shanghai 200032, Peoples R China
推荐引用方式
GB/T 7714		 Yin, Limin,Zhou, Jianhui,Li, Tianyou,et al. Inhibition of the dopamine transporter promotes lysosome biogenesis and ameliorates Alzheimer's disease-like symptoms in mice[J]. ALZHEIMERS & DEMENTIA,2022:15.
APA Yin, Limin.,Zhou, Jianhui.,Li, Tianyou.,Wang, Xinghua.,Xue, Wenlong.,...&Li, Yang.(2022).Inhibition of the dopamine transporter promotes lysosome biogenesis and ameliorates Alzheimer's disease-like symptoms in mice.ALZHEIMERS & DEMENTIA,15.
MLA Yin, Limin,et al."Inhibition of the dopamine transporter promotes lysosome biogenesis and ameliorates Alzheimer's disease-like symptoms in mice".ALZHEIMERS & DEMENTIA (2022):15.

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来源：上海药物研究所

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