Journal
PROGRESS IN RETINAL AND EYE RESEARCH
Volume 55, Issue -, Pages 149-181Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.preteyeres.2016.08.002
Keywords
Optineurin; Glaucoma; TANK binding kinase I (TBK1); Knock-in mouse iPS cells; Retinal ganglion cells; TBK1 inhibitor; BX795; Amlexanox
Categories
Funding
- Japanese Ministry of Health, Labour and Welfare [H18-KANKAKU-IPPAN-002, H22-KANKAKU-IPPAN-002, H26-ITAKU(NAN)-IPPAN-087]
- Japan Agency for Medical Research and Development [16ek0109072h0003]
- Japan Society for the Promotion of Science [16591779, 21390471, 24791885, 26861481]
- Grants-in-Aid for Scientific Research [16591779, 26861481, 21390471, 24791885] Funding Source: KAKEN
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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 et al. 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-icB 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 E5OK 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 E5OK 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 RGC5 in Optn E5OK knock-in mice. (C) 2016 Elsevier Ltd. All rights reserved.
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