Aromatic-turmerone 類縁体がシャペロン介在性オートファジー及びミクロオートファジー活性に及ぼす影響

抄録

Autophagy-lysosome proteolysis regulates protein homeostasis in neurons and is classified into macroautophagy, microautophagy (mA), and chaperone-mediated autophagy (CMA). Among them, we focused on CMA and mA and established a novel method to monitor CMA/mA activity. Recently, we identified an aromatic (ar)-turmerone analog (A2) that protects dopaminergic neurons via the activation of an antioxidant transcription factor, Nrf2, which is known to activate CMA/mA. In this study, we attempted to identify novel ar-turmerone analogs that can activate Nrf2 and CMA/mA more potently than A2. We synthesized four novel ar-turmerone analogues (A4-A7) and investigated their abilities to activate Nrf2 and CMA/mA. Immunoblot experiments revealed that all compounds significantly upregulated Nrf2 in SH-SY5Y cells. In contrast, only A4 significantly activated CMA/mA. To investigate why these analogs differently affected CMA/mA activity, we focused on p38 that regulates CMA via the phosphorylation of LAMP2A. Among ar-turmerone analogs that we investigated, only A4 induced the persistent activation of p38. In addition, experiments using inhibitors revealed that CMA/mA activation by A4 is mainly mediated by p38 activation. Taken together, we identified a novel ar-turmerone analog (A4) that activate CMA/mA via the sustained activation of p38.