Complement modulation reverses pathology in Y402H-retinal pigment epithelium cell model of age-related macular degeneration by restoring lysosomal function

Edvinas Cerniauskas, Merzena Kurzawa-Akanbi, Long Xie, Dean Hallam, Kathryn White, David Steel, Mary Doherty, Phillip D Whitfield, Jumana Al-Amani, Lyle Armstrong, David Kavanagh, John Lambris, Victor Korolchik, Claire Harris, Majilinda Lako

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)
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Abstract

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.
Original languageEnglish
Pages (from-to)1585-1603
Number of pages20
JournalStem Cells Translational Medicine
Volume9
Issue number12
DOIs
Publication statusPublished - 20 Aug 2020

Keywords

  • utophagy
  • C3
  • C3b
  • C5b-9
  • complement activation
  • complement factor H
  • human induced pluripotent stem cells
  • lysosome
  • retinal pigment epithelium
  • Y402H polymorphism

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