Inhibition of the dopamine transporter promotes lysosome biogenesis and ameliorates Alzheimer's disease-like symptoms in mice
Inhibition of the dopamine transporter promotes lysosome biogenesis and ameliorates Alzheimer's disease-like symptoms in mice
复制标题
抑制多巴胺转运蛋白可促进溶酶体生物发生并改善小鼠的阿尔茨海默病样症状。
DOI：
10.1002/alz.12776
复制
发表时间：
2022-09-21
影响因子：
14
通讯作者：
Li, Yang
中科院分区：
文献类型：
--
作者：
Yin, Limin;Zhou, Jianhui;Li, Yang
介绍溶酶体是维持细胞内稳态和蛋白质质量控制的降解细胞器。转录因子EB（TFEB）介导的溶酶体生物合成增强溶酶体依赖性降解和神经退行性疾病，但TFEB调控和修饰的机制仍然知之甚少。方法通过筛选新的小分子化合物，我们确定了一组溶酶体增强化合物（LYECs），促进TFEB激活和溶酶体生物合成。结果其中一种化合物LH 2 -051对多巴胺转运蛋白（DAT）的功能有明显的抑制作用，并促进溶酶体的生物合成。我们发现细胞周期蛋白依赖性激酶9（CDK 9）作为DAT介导的溶酶体生物发生的一种新的调节剂，并确定了TFEB上六个新的CDK 9磷酸化位点。我们观察到DAT-CDK 9-TFEB轴的信号转导发生在溶酶体上。最后，我们发现LH 2 -051增强了淀粉样β斑块的降解，并改善了淀粉样前体蛋白（APP）/早老素1（PS1）小鼠的记忆。讨论我们鉴定了DAT-CDK 9-TFEB信号传导轴作为溶酶体生物发生的新调节剂。我们的研究揭示了病理生理条件下蛋白质质量控制的机制。
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.