LOXL1 folding in exfoliation glaucoma.
LOXL1 folding in exfoliation glaucoma.
复制标题
去角色青光眼中的LOXL1折叠。
DOI：
10.1016/bs.apcsb.2019.09.005
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发表时间：
2019
影响因子：
--
通讯作者：
Wolosin JM
中科院分区：
文献类型：
--
作者：
Bernstein AM;Ritch R;Wolosin JM
剥脱综合征（XFS）是一种与年龄相关的疾病，其定义为聚集的纤维物质（XFM）沉积在细胞周围空间。主要发病发生在眼睛中，其中XFM积聚在前眼组织上。GWAS已经发现赖氨酰氧化酶样1（LOXL 1）的某些遗传变异体，弹性纤维形成所需的基质交联酶赋予XFS发展的风险，但不是单一的致病因素，因为许多受遗传影响的个体不会发展XFS或随后的青光眼（XFG）。我们发现XFG细胞在溶酶体、微管、自噬和线粒体中显示出缺陷，类似于在来自年龄相关综合征（例如主要的神经退行性疾病）的细胞中发现的缺陷。在大多数这些疾病中，决定性细胞因子是含有固有无序区（IDR）并显示出高聚集倾向的蛋白质。我们已经发现，在XFG患者来源的细胞中，LOXL 1蛋白积极进行自噬清除，表明LOXL 1正在发生聚集。计算机模拟分析表明，LOXL 1的前369个氨基酸构成了一个IDR，其中最高的紊乱概率峰集中在已知的风险位置。在实验上，我们发现未修饰的LOXL 1或保留良好结构的N-末端的荧光嵌合体的过表达引起大量的细胞内聚集，并且当高IDR峰被删除时，聚集减弱。总的来说，我们的工作表明，XFS/G的结果从LOXL 1蛋白的聚集加上细胞蛋白质稳定能力的下降，在一个长期积累的LOXL 1含有蛋白质聚集。
Exfoliation syndrome (XFS) is an age-related disease defined by the deposition of aggregated fibrous material (XFM) in the peri-cellular space. Principal morbidity occurs in the eye, where XFM accumulates on the anterior ocular tissues. GWAS have found that certain genetic variants of lysyl oxidase-like 1 (LOXL1), a matrix cross-linking enzyme that is required for elastic fiber formation confer risk for the development of XFS, but are not a single causative factor as many genetically affected individuals do not develop XFS or subsequent glaucoma (XFG). We have found that XFG cells display defects in lysosomes, microtubules, autophagy, and mitochondria resembling defects found in cells from age-related syndromes, such as the main neurodegenerative diseases. In the majority of these diseases, the determining cellular factor is a protein containing intrinsically disordered regions (IDRs) and displaying a high propensity for aggregation. We have found that in XFG patient-derived cells, LOXL1 protein is actively subjected to autophagic clearance, suggesting that LOXL1 is undergoing aggregation. In silico analysis demonstrates that LOXL1’s first 369 aa constitute an IDR with the highest disorder probability peak centering around the known risk positions. Experimentally, we have found over-expression of either unmodified LOXL1 or fluorescent chimeras preserving the well-structured N-terminus cause copious intracellular aggregation and that aggregation wanes when the high IDR peaks are deleted. Overall, our work suggests that XFS/G results from the aggregation of the LOXL1 protein coupled with a reduction of cellular proteostasis capabilities in aging, resulting in a chronic build-up of LOXL1-containing protein aggregates.
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影响因子：
34.7
作者：
Frost, Bess;Diamond, Marc I.
通讯作者：
Diamond, Marc I.
影响因子：
2
作者：
Konstas, Anastasios G P;Ringvold, Amund
通讯作者：
Ringvold, Amund
影响因子：
1.2
作者：
de Juan-Marcos, Lourdes;Escudero-Dominguez, Francisco A.;Gonzalez-Sarmiento, Rogelio
通讯作者：
Gonzalez-Sarmiento, Rogelio
LOXL1基因中的DNA序列变异与具有广泛种族多样性的美国诊所人群中的伪脱糖青光眼有关。
影响因子：
--
作者：
Fan, Bao Jian;Pasquale, Louis;Grosskreutz, Cynthia L.;Rhee, Douglas;Chen, Teresa;DeAngelis, Margaret M.;Kim, Ivana;Del Bono, Elizabeth;Miller, Joan W.;Li, Tiansen;Haines, Jonathan L.;Wiggs, Janey L.
通讯作者：
Wiggs, Janey L.
影响因子：
4.2
作者：
Hayashi, Hisako;Gotoh, Norimoto;Yoshimura, Nagahisa
通讯作者：
Yoshimura, Nagahisa