溶酶体是细胞内必不可少的降解细胞器和信号枢纽,在巨自噬/自噬的调节中起着至关重要的作用。溶酶体功能异常和自噬受损与多种神经退行性疾病的发生发展密切相关。增强溶酶体活性和提高自噬水平有望成为治疗这些疾病的有效策略。然而,仍然缺乏动态调节活细胞或动物中溶酶体活性和自噬水平的方法.在我们最近的工作中,我们应用光遗传学来操纵溶酶体的生理和功能,开发三种溶酶体靶向光遗传学工具:lyso-NpHR3.0,lyso-ArchT,还有lyso-ChR2.这些新的执行器能够对光依赖性调节关键方面,如溶酶体膜电位,内腔pH值,水解酶活性,降解过程,和活细胞中的Ca2+动力学。值得注意的是,lyso-ChR2激活通过MTOR途径诱导自噬,而在阿尔茨海默病细胞模型中通过自噬诱导促进Aβ清除。此外,lyso-ChR2激活可减少Aβ沉积并减轻Aβ诱导的阿尔茨海默病秀丽隐杆线虫模型中的麻痹。我们的溶酶体光遗传学执行器提供了一种动态调节活细胞和动物中溶酶体生理和自噬活性的新方法。
Lysosomes are essential degradative organelles and signaling hubs within cells, playing a crucial role in the regulation of macroautophagy/autophagy. Dysfunction of lysosomes and impaired autophagy are closely associated with the development of various neurodegenerative diseases. Enhancing lysosomal activity and boosting autophagy levels holds great promise as effective strategies for treating these diseases. However, there remains a lack of methods to dynamically regulate lysosomal activity and autophagy levels in living cells or animals. In our recent work, we applied
optogenetics to manipulate lysosomal physiology and function, developing three lysosome-targeted optogenetic tools: lyso-NpHR3.0, lyso-ArchT, and lyso-ChR2. These new actuators enable light-dependent regulation of key aspects such as lysosomal membrane potential, lumenal pH, hydrolase activity, degradation processes, and Ca2+ dynamics in living cells. Notably, lyso-ChR2 activation induces autophagy via the MTOR pathway while it promotes Aβ clearance through autophagy induction in cellular models of Alzheimer disease. Furthermore, lyso-ChR2 activation reduces Aβ deposition and alleviates Aβ-induced paralysis in Caenorhabditis elegans models of Alzheimer disease. Our lysosomal optogenetic actuators offer a novel method for dynamically regulating lysosomal physiology and autophagic activity in living cells and animals.