Moos Walter H, Faller Douglas V, Glavas Ioannis P, Harpp David N, Kanara Iphigenia, Mavrakis Anastasios N, Pernokas Julie, Pernokas Mark, Pinkert Carl A, Powers Whitney R, Sampani Konstantina, Steliou Kosta, Vavvas Demetrios G, Zamboni Robert J, Kodukula Krishna, Chen Xiaohong
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, San Francisco, California.
ShangPharma Innovation, Inc., South San Francisco, California.
Biores Open Access. 2020 Mar 31;9(1):94-105. doi: 10.1089/biores.2020.0004. eCollection 2020.
In this review we outline a rationale for identifying neuroprotectants aimed at inducing endogenous Klotho activity and expression, which is epigenetic action, by definition. Such an approach should promote remyelination and/or stimulate myelin repair by acting on mitochondrial function, thereby heralding a life-saving path forward for patients suffering from neuroinflammatory diseases. Disorders of myelin in the nervous system damage the transmission of signals, resulting in loss of vision, motion, sensation, and other functions depending on the affected nerves, currently with no effective treatment. genes and their single-pass transmembrane Klotho proteins are powerful governors of the threads of life and death, true to the origin of their name, Fates, in Greek mythology. Among its many important functions, Klotho is an obligatory co-receptor that binds, activates, and/or potentiates critical fibroblast growth factor activity. Since the discovery of a little over two decades ago, it has become ever more apparent that when Klotho pathways go awry, oxidative stress and mitochondrial dysfunction take over, and age-related chronic disorders are likely to follow. The physiological consequences can be wide ranging, potentially wreaking havoc on the brain, eye, kidney, muscle, and more. Central nervous system disorders, neurodegenerative in nature, and especially those affecting the myelin sheath, represent worthy targets for advancing therapies that act upon Klotho pathways. Current drugs for these diseases, even therapeutics that are disease modifying rather than treating only the symptoms, leave much room for improvement. It is thus no wonder that this topic has caught the attention of biomedical researchers around the world.
在本综述中，我们概述了一种确定神经保护剂的基本原理，这些神经保护剂旨在诱导内源性α-klotho活性和表达，从定义上讲，这是一种表观遗传作用。这种方法应通过作用于线粒体功能来促进髓鞘再生和/或刺激髓鞘修复，从而为患有神经炎症性疾病的患者开辟一条挽救生命的前进道路。神经系统中的髓鞘紊乱会损害信号传递，导致视力、运动、感觉以及其他取决于受影响神经的功能丧失，目前尚无有效治疗方法。α-klotho基因及其单次跨膜的α-klotho蛋白是生死命运的强大主宰，名副其实，其名字源于希腊神话中的命运女神。在其众多重要功能中，α-klotho是一种必需的共受体，可结合、激活和/或增强关键的成纤维细胞生长因子活性。自二十多年前发现α-klotho以来，越来越明显的是，当α-klotho信号通路出现紊乱时，氧化应激和线粒体功能障碍就会占据主导，随后可能会出现与年龄相关的慢性疾病。其生理后果可能广泛多样，可能对大脑、眼睛、肾脏、肌肉等造成严重破坏。本质上具有神经退行性的中枢神经系统疾病，尤其是那些影响髓鞘的疾病，是推进作用于α-klotho信号通路的治疗方法的有价值靶点。目前用于这些疾病的药物，即使是那些改变疾病进程而非仅治疗症状的疗法，仍有很大的改进空间。因此，难怪这个话题引起了世界各地生物医学研究人员的关注。
