Exfoliation Syndrome: A Disease of Autophagy and LOXL1 Proteopathy.
Exfoliation Syndrome: A Disease of Autophagy and LOXL1 Proteopathy.
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DOI：
10.1097/ijg.0000000000000919
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发表时间：
2018-07
影响因子：
2
通讯作者：
Wolosin JM
中科院分区：
文献类型：
--
作者：
Bernstein AM;Ritch R;Wolosin JM
脱落综合征（XFS）是一种与年龄相关的疾病，涉及合成弹性纤维的组织中聚集性纤维物质（XFM）在细胞外基质上的沉积。其主要发病于眼睛，XFM在睫状体、虹膜和晶状体表面积聚。剥脱性青光眼（XFG）发生在XFS患者的高比例，可以是一个快速发展的疾病。在世界范围内，XFG型约占开角型青光眼病例的25%。XFS和XFG表现出明显的年龄依赖性，类似于许多被归类为聚集病的年龄相关疾病。由于缺乏实验模型，对XFS/G细胞基础的了解进展缓慢。通过对XFG患者小梁切除术后获得的原代人腱成纤维细胞（TF）和年龄匹配的POAG对照进行研究，我们发现XFG细胞中的TF表现出许多在其他蛋白质聚集性疾病（如帕金森病、阿尔茨海默病、亨廷顿病和年龄相关性黄斑变性）细胞中观察到的功能特征。我们已经记录了溶酶体定位、微管组织、自噬加工速率和线粒体健康方面的缺陷。关于溶酶体和自噬体在XFG细胞中的定位失败，我们发现XFG TF无法建立跨核微管组织中心，而这是沿微管进行有效向心泡运动所必需的。关于自噬功能障碍的潜在来源，我们将注意力集中在赖氨酸氧化酶样1蛋白（LOXL1）的潜在作用上，这种弹性纤维催化剂与XFG风险表现出变异依赖关系。我们的实验表明，a)在XFG细胞中，大量的LOXL1被自噬系统处理降解；b)大部分LOXL1 n端结构域处于高度无序状态，这种状态会大大增加多肽错误折叠的频率；c)最大错误折叠发生在高危变异体G153D所在的153氨基酸位置；d)用天冬氨酸(d)代替甘氨酸(G)会导致20个氨基酸周围结构域内紊乱的显著减少。最后，我们发现聚簇蛋白，一种可以由细胞内或细胞外聚集体诱导的蛋白质，在XFG - TF中均匀过表达。我们的研究结果对XFG与细胞聚集病相关理论的影响进行了讨论。
Exfoliation syndrome (XFS) is an age-related disease involving the deposition of aggregated fibrillar material (XFM) at extracellular matrices in tissues that synthesize elastic fibers. Its main morbidity is in the eye, where XFM accumulations form on the surface of the ciliary body, iris and lens. Exfoliation glaucoma (XFG) occurs in a high proportion of persons with XFS and can be a rapidly progressing disease. Worldwide, XFG accounts for about 25% of open-angle glaucoma cases. XFS and XFG show a sharp age-dependence, similarly to the many age-related diseases classified as aggregopathies. Progress in understanding the cellular bases for XFS/G has been slowed by a lack of experimental models. Working with primary human tenon fibroblasts (TF) derived from trabeculectomies of XFG patients and age-matched POAG controls, we found that TF from XFG cells display many of the functional features observed in cells from other protein aggregate diseases, such as Parkinson’s, Alzheimer’s, Huntington’s and age-related macular degeneration. We have documented defects in lysosomal positioning, microtubule organization, autophagy processing rate and mitochondrial health. In regard to failure of lysosomal and autophagosome positioning in XFG cells, we have found that XFG TF are unable to establish the trans-nuclear microtubule organizing center that is required for efficient centripetal vesicular locomotion along microtubules. In regard to potential sources of the autophagy malfunction, we have directed our attention to a potential role of the lysyl oxidase-like 1 protein (LOXL1), the elastic fiber catalyst that displays variant-dependent association with risk for XFG. Our experiments show that a) in XFG cells, a substantial fraction of LOXL1 is processed for degradation by the autophagic system; b) most of the LOXL1 N-terminus domain exists in a highly disordered state, a condition known to greatly increase the frequency of polypeptide misfolding; c) that maximum misfolding occurs at amino acid position 153, the location of the high risk variant G153D; and d) that replacement of glycine (G) by aspartate (D) there results in a substantial decrease in disorder within the 20 amino acid surrounding domain. Finally, we show that clusterin, a protein that can be induced by the presence of intra-, or extra-cellular aggregates, is uniformly overexpressed in XFG TF. The implications of our results for a theory relating XFG to cellular aggregopathy are discussed.