心肌蛋白错误折叠与青光眼:20年最新研究

IF 18.6 1区 医学 Q1 OPHTHALMOLOGY Progress in Retinal and Eye Research Pub Date : 2023-07-01 DOI:10.1016/j.preteyeres.2023.101188
Emily G. Saccuzzo, Hannah A. Youngblood, Raquel L. Lieberman
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引用次数: 0

摘要

MYOC基因突变约占原发性开角型青光眼(POAG)病例的5%。MYOC编码蛋白mycoilin,这是一种由N-末端卷曲螺旋(CC)和亮氨酸拉链(LZ)结构域组成的多聚体分泌糖蛋白,它们通过无序的接头连接到30kDa嗅觉素(OLF)结构域。90%以上引起青光眼的突变定位于OLF结构域。虽然肌细胞膜蛋白在许多组织中表达,但突变型肌细胞膜仅与眼睛前部小梁网的疾病有关。主要的致病机制涉及毒性功能的获得,即突变的肌球蛋白在细胞内聚集而不是分泌,这会导致细胞应激和TM细胞死亡、眼压升高和随后的青光眼相关视网膜变性的早期时间线。在这篇综述中,我们重点介绍了我们实验室在过去~15年中为增强我们对肌细胞膜蛋白相关青光眼的分子理解所做的工作,其中包括突变肌细胞膜形成的聚集体的分子结构和性质的细节。最后,我们讨论了一些悬而未决的问题,如仅从基因型预测表型、肌细胞膜蛋白难以捉摸的天然功能以及我们的工作所能实现的翻译方向。
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Myocilin misfolding and glaucoma: A 20-year update

Mutations in the gene MYOC account for approximately 5% of cases of primary open angle glaucoma (POAG). MYOC encodes for the protein myocilin, a multimeric secreted glycoprotein composed of N-terminal coiled-coil (CC) and leucine zipper (LZ) domains that are connected via a disordered linker to a 30 kDa olfactomedin (OLF) domain. More than 90% of glaucoma-causing mutations are localized to the OLF domain. While myocilin is expressed in numerous tissues, mutant myocilin is only associated with disease in the anterior segment of the eye, in the trabecular meshwork. The prevailing pathogenic mechanism involves a gain of toxic function whereby mutant myocilin aggregates intracellularly instead of being secreted, which causes cell stress and an early timeline for TM cell death, elevated intraocular pressure, and subsequent glaucoma-associated retinal degeneration. In this review, we focus on the work our lab has conducted over the past ∼15 years to enhance our molecular understanding of myocilin-associated glaucoma, which includes details of the molecular structure and the nature of the aggregates formed by mutant myocilin. We conclude by discussing open questions, such as predicting phenotype from genotype alone, the elusive native function of myocilin, and translational directions enabled by our work.

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来源期刊
CiteScore
34.10
自引率
5.10%
发文量
78
期刊介绍: Progress in Retinal and Eye Research is a Reviews-only journal. By invitation, leading experts write on basic and clinical aspects of the eye in a style appealing to molecular biologists, neuroscientists and physiologists, as well as to vision researchers and ophthalmologists. The journal covers all aspects of eye research, including topics pertaining to the retina and pigment epithelial layer, cornea, tears, lacrimal glands, aqueous humour, iris, ciliary body, trabeculum, lens, vitreous humour and diseases such as dry-eye, inflammation, keratoconus, corneal dystrophy, glaucoma and cataract.
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