Open AccessComplement modulation reverses pathology in Y402H ‐retinal pigment epithelium cell model of age‐related macular degeneration by restoring lysosomal function
Author(s) -
Cerniauskas Edvinas,
KurzawaAkanbi Marzena,
Xie Long,
Hallam Dean,
MoyaMolina Marina,
White Kathryn,
Steel David,
Doherty Mary,
Whitfield Phil,
AlAama Jumana,
Armstrong Lyle,
Kavanagh David,
Lambris John D.,
Korolchuk Viktor I.,
Harris Claire,
Lako Majlinda
Publication year - 2020
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.1002/sctm.20-0211
Subject(s) - drusen , macular degeneration , retinal pigment epithelium , factor h , lysosome , lipofuscin , complement system , microbiology and biotechnology , retinal , biology , pathology , immunology , medicine , biochemistry , ophthalmology , antibody , enzyme
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.