Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy.
Retinal Degeneration In A Mouse Model Of CLN5 Disease Is Associated With Compromised Autophagy.
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DOI：
10.1038/s41598-017-01716-1
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发表时间：
2017-05-09
影响因子：
4.6
通讯作者：
Kanninen KM
中科院分区：
文献类型：
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作者：
Leinonen H;Keksa-Goldsteine V;Ragauskas S;Kohlmann P;Singh Y;Savchenko E;Puranen J;Malm T;Kalesnykas G;Koistinaho J;Tanila H;Kanninen KM
晚期婴儿神经元蜡样质脂褐质沉积症（CLN 5疾病）的芬兰变体属于神经元蜡样质脂褐质沉积症（NCL）疾病家族。视力丧失是儿童形式的NCL的第一个临床体征之一。CLN 5突变是CLN 5疾病的基础。这项研究的目的是表征CLN 5蛋白缺乏正常功能如何影响小鼠视网膜。暗视视网膜电图（ERG）显示，在1月龄时，CLN 5缺陷小鼠的c波振幅已经降低，表明视网膜色素上皮中的病理事件。A波和B波分别从2月龄和3月龄开始出现进行性损害。结构和免疫组织化学（IHC）分析显示优先损害的光感受器，积累的自发荧光存储材料，细胞凋亡的光感受器，和强烈的炎症在CLN 5缺陷小鼠视网膜。自噬相关蛋白Beclin-1和P62的水平增加，并增加LC 3b-II/LC 3b-I的比例，通过Western印迹检测整个视网膜提取物。明视ERG、视觉诱发电位、IHC和细胞计数表明与视杆相比，视锥光感受器存活时间相对较长。总之，CLN 5缺陷型小鼠出现早期视力丧失，反映了临床儿童期NCL形式中报告的状况。CLN 5缺陷小鼠的视力丧失主要是由感光细胞变性引起的。
The Finnish variant of late infantile neuronal ceroid lipofuscinosis (CLN5 disease) belongs to a family of neuronal ceroid lipofuscinosis (NCLs) diseases. Vision loss is among the first clinical signs in childhood forms of NCLs. Mutations in CLN5 underlie CLN5 disease. The aim of this study was to characterize how the lack of normal functionality of the CLN5 protein affects the mouse retina. Scotopic electroretinography (ERG) showed a diminished c-wave amplitude in the CLN5 deficient mice already at 1 month of age, indicative of pathological events in the retinal pigmented epithelium. A- and b-waves showed progressive impairment later from 2 and 3 months of age onwards, respectively. Structural and immunohistochemical (IHC) analyses showed preferential damage of photoreceptors, accumulation of autofluorescent storage material, apoptosis of photoreceptors, and strong inflammation in the CLN5 deficient mice retinas. Increased levels of autophagy-associated proteins Beclin-1 and P62, and increased LC3b-II/LC3b-I ratio, were detected by Western blotting from whole retinal extracts. Photopic ERG, visual evoked potentials, IHC and cell counting indicated relatively long surviving cone photoreceptors compared to rods. In conclusion, CLN5 deficient mice develop early vision loss that reflects the condition reported in clinical childhood forms of NCLs. The vision loss in CLN5 deficient mice is primarily caused by photoreceptor degeneration.