Inhibition of the dopamine transporter promotes lysosome biogenesis and ameliorates Alzheimer's disease–like symptoms in mice
| Autor: | Limin Yin, Jianhui Zhou, Tianyou Li, Xinghua Wang, Wenlong Xue, Jie Zhang, Lingxi Lin, Ning Wang, Xinyi Kang, Yu Zhou, Hong Liu, Yang Li |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Alzheimer's & Dementia. 19:1343-1357 |
| ISSN: | 1552-5279 1552-5260 |
| DOI: | 10.1002/alz.12776 |
| Popis: | 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.By screening novel small-molecule compounds, we identified a group of lysosome-enhancing compounds (LYECs) that promote TFEB activation and lysosome biogenesis.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.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. |
| Databáze: | OpenAIRE |
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