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

Abstract 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.