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Lookup NU author(s): Edvinas Cerniauskas, Dr Marzena Kurzawa-Akanbi, Dr Long Xie, Dr Dean Hallam, Marina Moya Molina, David Steel, Professor Lyle Armstrong, Professor David KavanaghORCiD, Professor Viktor KorolchukORCiD, Professor Claire Harris, Professor Majlinda LakoORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Age related macular degeneration (AMD) is a multifactorial disease, which is characterised 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 characterised 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 internalisation 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.
Author(s): 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 J, Korolchuk V, Harris C, Lako M
Publication type: Article
Publication status: Published
Journal: Stem Cells Translational Medicine
Year: 2020
Volume: 9
Issue: 12
Pages: 1585-1603
Print publication date: 01/12/2020
Online publication date: 20/08/2020
Acceptance date: 12/07/2020
Date deposited: 25/11/2020
ISSN (print): 2157-6564
ISSN (electronic): 2157-6580
Publisher: Wiley
URL: https://doi.org/10.1002/sctm.20-0211
DOI: 10.1002/sctm.20-0211
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