Targeting the ER-autophagy system in the trabecular meshwork to treat glaucoma.
Targeting the ER-autophagy system in the trabecular meshwork to treat glaucoma.
复制标题
针对小梁网中的ER-自助系统来治疗青光眼。
DOI：
10.1016/j.exer.2015.08.017
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发表时间：
2016-03
影响因子：
3.4
通讯作者：
Dickey CA
中科院分区：
文献类型：
--
作者：
Stothert AR;Fontaine SN;Sabbagh JJ;Dickey CA
房水动力学涉及的一个主要引流网络是传统的流出通道，它由小梁网络(TM)门控。TM起到了分子筛的作用，提供了对房水流出的抵抗，这负责调节眼压(IOP)。如果TM受损，房水流出受损，眼压升高，可能会出现青光眼。MYOC基因突变通过促进内质网(ER)中肌球蛋白的异常淀粉样变性，导致内质网应激诱导TM细胞死亡，从而导致遗传性原发性开角型青光眼(POAG)。大约70%-80%的青光眼患者可以观察到霉菌素的蓄积，这表明环境或其他遗传因素也可能促进霉菌素的毒性。例如，简单地阻止肌红素糖基化就足以促进其异常增加。这些肌球蛋白淀粉样蛋白是独一无二的，因为没有其他已知的致病蛋白积累在TM细胞的ER内并造成毒性。此外，尽管这种蛋白在其他类型的细胞中表达，但这种致病积累只杀死了TM细胞，这表明TM特有的另一种修饰物参与了霉菌素的蛋白毒性。内质网自噬(网状吞噬)是霉菌毒素清除的重要途径之一，受年龄和营养等其他环境因素的影响很大。本综述将讨论霉菌素和自噬之间的联系，评估这一降解途径在青光眼中的作用及其作为治疗靶点的潜力。
A major drainage network involved in aqueous humor dynamics is the conventional outflow pathway, which is gated by the trabecular meshwork (TM). The TM acts as a molecular sieve, providing resistance to aqueous outflow, which is responsible for regulating intraocular pressure (IOP). If the TM is damaged, aqueous outflow is impaired, IOP increases and glaucoma can manifest. Mutations in the MYOC gene cause hereditary primary open-angle glaucoma (POAG) by promoting the abnormal amyloidosis of the myocilin protein in the endoplasmic reticulum (ER), leading to ER stress-induced TM cell death. Myocilin accumulation is observed in approximately 70–80% of all glaucoma cases suggesting that environmental or other genetic factors may also promote myocilin toxicity. For example, simply preventing myocilin glycosylation is sufficient to promote its abnormal accretion. These myocilin amyloids are unique as there are no other known pathogenic proteins that accumulate within the ER of TM cells and cause toxicity. Moreover, this pathogenic accumulation only kills TM cells, despite expression of this protein in other cell types, suggesting that another modifier exclusive to the TM participates in the proteotoxicity of myocilin. ER autophagy (reticulophagy) is one of the pathways essential for myocilin clearance that can be impacted dramatically by aging and other environmental factors such as nutrition. This review will discuss the link between myocilin and autophagy, evaluating the role of this degradation pathway in glaucoma as well as its potential as a therapeutic target.