Complement modulation reverses pathology in Y402H-retinal pigment epithelium cell model of age-related macular degeneration by restoring lysosomal function.
Complement modulation reverses pathology in Y402H-retinal pigment epithelium cell model of age-related macular degeneration by restoring lysosomal function.
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DOI：
10.1002/sctm.20-0211
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发表时间：
2020-12
影响因子：
6
通讯作者：
Lako M
中科院分区：
文献类型：
--
作者：
Cerniauskas E;Kurzawa-Akanbi M;Xie L;Hallam D;Moya-Molina M;White K;Steel D;Doherty M;Whitfield P;Al-Aama J;Armstrong L;Kavanagh D;Lambris JD;Korolchuk VI;Harris C;Lako M
年龄相关性黄斑变性(AMD)是一种多因素疾病，以中心视力丧失为特征，75岁前每三人中就有一人受到影响。补体因子H(CFH)基因Y402H多态性显著增加AMD的风险。我们发现Y402H-AMD患者特有的视网膜色素上皮(RPE)细胞的特征是黑素小体数量显著减少，肿胀的溶酶体样囊泡数量增加，膜脆弱，组织蛋白酶D渗入玻璃膜样沉积，溶酶体功能降低。在高危RPE细胞中，C3的周转显著增加，导致末端补体复合体C5b-9在溶酶体处更高的内化和沉积。通过comstatin类似物Cp40抑制C3的加工可以通过减轻溶酶体的负担和恢复其功能来逆转疾病的表型。这些发现表明，调节补体系统是治疗与补体调节失调相关的AMD患者的有效方法。Y402H-AMD RPE细胞自噬-溶酶体途径功能障碍的示意图以及Cp40在恢复溶酶体功能中的作用。
Age‐related macular degeneration (AMD) is a multifactorial disease, which is characterized by loss of central vision, affecting one in three people by the age of 75. The Y402H polymorphism in the complement factor H (CFH) gene significantly increases the risk of AMD. We show that Y402H‐AMD‐patient‐specific retinal pigment epithelium (RPE) cells are characterized by a significant reduction in the number of melanosomes, an increased number of swollen lysosome‐like‐vesicles with fragile membranes, Cathepsin D leakage into drusen‐like deposits and reduced lysosomal function. The turnover of C3 is increased significantly in high‐risk RPE cells, resulting in higher internalization and deposition of the terminal complement complex C5b‐9 at the lysosomes. Inhibition of C3 processing via the compstatin analogue Cp40 reverses the disease phenotypes by relieving the lysosomes of their overburden and restoring their function. These findings suggest that modulation of the complement system represents a useful therapeutic approach for AMD patients associated with complement dysregulation. Schematic presentation of autophagy‐lysosomal pathway dysfunction in Y402H‐AMD RPE cells and the impact of Cp40 in restoring the lysosomal function.
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影响因子：
32.4
作者：
Hess C;Kemper C
通讯作者：
Kemper C
影响因子：
4.6
作者：
Fernandez-Godino R;Pierce EA
通讯作者：
Pierce EA
影响因子：
29
作者：
King, Ben C.;Kulak, Klaudia;Blom, Anna M.
通讯作者：
Blom, Anna M.
影响因子：
3.4
作者：
Gouras, Peter;Brown, Kristy;Neuringer, Martha
通讯作者：
Neuringer, Martha
DOI：
10.4049/jimmunol.1500937
发表时间：
2015-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Georgiannakis A;Burgoyne T;Lueck K;Futter C;Greenwood J;Moss SE
通讯作者：
Moss SE