Minegishi Y, Nakayama M, Iejima D, et al.
期刊名称：Progress in Retinal and Eye Research
青光眼 意义 疾病
摘要：青光眼是双眼失明的主要原因之一，影响全球近5700万人。青光眼的特征是视网膜神经节细胞的进行性丧失，并且通常与眼内压（IOP）相关。正常眼压性青光眼（NTG），特点是IOP正常，但表现为进行性青光眼，尚未完全理解。 2002年，Sarfarazi等人确定了与遗传性NTG有关的FIP-2基因突变，将该基因重命名为“optineurin”（OPTN）。全世界多个小组的进一步调查显示，OPTN涉及几个关键的细胞功能，如NF-κB调节，自噬和囊泡运输。最近，OPTN突变被发现可引起肌萎缩性侧索硬化（ALS）。令人惊讶的是，OPTN相互作用蛋白中的突变，如TANK结合蛋白1（TBK1）基因重复，也可以引起NTG和ALS。现在，这两个基因将这些表型不同的神经元疾病合并成一种常见的病理机制。 TBK1抑制剂已成为NTG的一种潜在治疗。在这篇文章中，我们重点研究了 OPTN E50K突变----NTG最常见的突变，旨在通过细胞和转基因小鼠中表达的Optn基因突变来描述NTG分子机制。培养患者的iPS细胞并分化成神经细胞以观察异常行为和E50K突变的影响。这些体外研究进一步确定了抑制剂BX795和amlexanox（其具有逆转患者神经细胞疾病表现的潜力）的作用。在这里，我们首次发现了amlexanox对Optn E50K敲除小鼠的RGC具有保护作用。
Glaucoma is one of the leading causes of bilateral blindness, affecting nearly 57 million people worldwide. Glaucoma is characterized by a progressive loss of retinal ganglion cells and is often associated with intraocular pressure (IOP). Normal tension glaucoma (NTG), marked by normal IOP but progressive glaucoma, is incompletely understood. In 2002, Sarfarazi etal. identified FIP-2 gene mutations responsible for hereditary NTG, renaming this gene "optineurin" (OPTN). Further investigations by multiple groups worldwide showed that OPTN is involved in several critical cellular functions, such as NF-κB regulation, autophagy, and vesicle transport. Recently, OPTN mutations were found to cause amyotrophic lateral sclerosis (ALS). Surprisingly, a mutation in the OPTN interacting protein, i.e., the duplication of TANK binding protein 1 (TBK1) gene, also can cause both NTG and ALS. These phenotypically distinct neuronal diseases are now merging into one common pathological mechanism by these two genes. TBK1 inhibition has emerged as a potential therapy for NTG. In this manuscript, we focus on the OPTN E50K mutation, the most common mutation for NTG, to describe the molecular mechanism of NTG by expressing a mutant Optn gene in cells and genetically modified mice. Patient iPS cells were developed and differentiated into neural cells to observe abnormal behavior and the impact of the E50K mutation. These in vitro studies were further extended to identify the inhibitors BX795 and amlexanox, which have the potential to reverse the disease-causing phenomenon in patient's neural cells. Here we show for the first time that amlexanox protects RGCs in Optn E50K knock-in mice.