Santoni Giorgio, Maggi Federica, Amantini Consuelo, Marinelli Oliviero, Nabissi Massimo, Morelli Maria Beatrice
Immunopathology Laboratory, School of Pharmacy, University of Camerino, Camerino, Italy.
Department of Molecular Medicine, Sapienza University, Rome, Italy.
Front Physiol. 2020 Mar 24;11:251. doi: 10.3389/fphys.2020.00251. eCollection 2020.
Mucolipins (TRPML) are endosome/lysosome Ca permeable channels belonging to the family of transient receptor potential channels. In mammals, there are three TRPML proteins, TRPML1, 2, and 3, encoded by genes. Among these channels, TRPML1 is a reactive oxygen species sensor localized on the lysosomal membrane that is able to control intracellular oxidative stress due to the activation of the autophagic process. Moreover, genetic or pharmacological inhibition of the TRPML1 channel stimulates oxidative stress signaling pathways. Experimental data suggest that elevated levels of reactive species play a role in several neurological disorders. There is a need to gain better understanding of the molecular mechanisms behind these neurodegenerative diseases, considering that the main sources of free radicals are mitochondria, that mitochondria/endoplasmic reticulum and lysosomes are coupled, and that growing evidence links neurodegenerative diseases to the gain or loss of function of proteins related to lysosome homeostasis. This review examines the significant roles played by the TRPML1 channel in the alterations of calcium signaling responsible for stress-mediated neurodegenerative disorders and its potential as a new therapeutic target for ameliorating neurodegeneration in our ever-aging population.
黏脂素（TRPML）是属于瞬时受体电位通道家族的内体/溶酶体钙通透性通道。在哺乳动物中，有三种由基因编码的TRPML蛋白，即TRPML1、2和3。在这些通道中，TRPML1是一种位于溶酶体膜上的活性氧传感器，能够通过自噬过程的激活来控制细胞内氧化应激。此外，TRPML1通道的基因或药理学抑制会刺激氧化应激信号通路。实验数据表明，活性物质水平升高在几种神经系统疾病中起作用。鉴于自由基的主要来源是线粒体，线粒体/内质网和溶酶体相互关联，且越来越多的证据将神经退行性疾病与溶酶体稳态相关蛋白的功能获得或丧失联系起来，因此有必要更好地了解这些神经退行性疾病背后的分子机制。本综述探讨了TRPML1通道在负责应激介导的神经退行性疾病的钙信号改变中所起的重要作用，以及其作为改善老年人群神经退行性变的新治疗靶点的潜力。
