Autophagy is a process leading to the degradation of cellular material, in organelles called lysosomes, to supply energy or generate building blocks for the synthesis of new materials. Over the past decades, its role has been evidenced in several indications, notably in neurodegenerative disorders and orphan diseases called lysosomal storage disorders and its modulation is largely envisioned as a therapeutic avenue to alleviate the symptoms and reverse the clinical courses of these indications. Identifying new chemical classes and drugs is, hence, of huge importance. In this study, we developed automated assays to assess the potential efficacy of chemical compounds on different steps of autophagy, notably its induction through the localization of a largely involved transcription factor, transcription factor EB (TFEB). These assays were then used to screen a collection of 1,520 approved drugs. This study led to the identification of five candidate hits modulating autophagy and TFEB subcellular localization. Our results suggest the repurposing potential of already approved drugs in central nervous system disorders with lysosomal storage impairments.

中文翻译：

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用于识别转录因子 EB 易位和自噬调节剂的自动化检测

自噬是导致细胞材料在称为溶酶体的细胞器中降解的过程，以提供能量或生成用于合成新材料的构件。在过去的几十年中，它的作用已在多种适应症中得到证实，特别是在称为溶酶体贮积症的神经退行性疾病和孤儿疾病中，其调节在很大程度上被设想为缓解症状和逆转这些适应症临床过程的治疗途径。因此，识别新的化学类别和药物非常重要。在这项研究中，我们开发了自动化测定法来评估化合物对自噬不同步骤的潜在功效，特别是通过定位一个主要涉及的转录因子转录因子 EB (TFEB) 来诱导它。然后使用这些检测方法筛选 1,520 种已获批准的药物。该研究确定了五种调节自噬和 TFEB 亚细胞定位的候选命中。我们的研究结果表明，已经批准的药物在溶酶体贮积障碍的中枢神经系统疾病中具有再利用潜力。