Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26


Mcharg, Selina, Booth, Laura, Perveen, Rahat, Garcia, Isabel Riba, Brace, Nicole, Bayatti, Nadhim, Sergouniotis, Panagiotis I, Phillips, Alexander M ORCID: 0000-0002-1637-4803, Day, Anthony J, Black, Graeme CM et al (show 4 more authors) (2022) Mast cell infiltration of the choroid and protease release are early events in age-related macular degeneration associated with genetic risk at both chromosomes 1q32 and 10q26. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 119 (20). e2118510119-.

[img] Text
547377_2_merged_1650304113.pdf - Author Accepted Manuscript
Download (31MB) | Preview

Abstract

Age-related macular degeneration (AMD) is a leading cause of visual loss. It has a strong genetic basis, and common haplotypes on chromosome (Chr) 1 (CFH Y402H variant) and on Chr10 (near HTRA1/ARMS2) contribute the most risk. Little is known about the early molecular and cellular processes in AMD, and we hypothesized that analyzing submacular tissue from older donors with genetic risk but without clinical features of AMD would provide biological insights. Therefore, we used mass spectrometry–based quantitative proteomics to compare the proteins in human submacular stromal tissue punches from donors who were homozygous for high-risk alleles at either Chr1 or Chr10 with those from donors who had protective haplotypes at these loci, all without clinical features of AMD. Additional comparisons were made with tissue from donors who were homozygous for high-risk Chr1 alleles and had early AMD. The Chr1 and Chr10 risk groups shared common changes compared with the low-risk group, particularly increased levels of mast cell–specific proteases, including tryptase, chymase, and carboxypeptidase A3. Histological analyses of submacular tissue from donors with genetic risk of AMD but without clinical features of AMD and from donors with Chr1 risk and AMD demonstrated increased mast cells, particularly the tryptase-positive/chymase-negative cells variety, along with increased levels of denatured collagen compared with tissue from low–genetic risk donors. We conclude that increased mast cell infiltration of the inner choroid, degranulation, and subsequent extracellular matrix remodeling are early events in AMD pathogenesis and represent a unifying mechanistic link between Chr1- and Chr10-mediated AMD.

Item Type: Article
Uncontrolled Keywords: age-related macular degeneration, proteomics, mast cells
Divisions: Faculty of Science and Engineering > School of Electrical Engineering, Electronics and Computer Science
Depositing User: Symplectic Admin
Date Deposited: 13 Jun 2022 15:51
Last Modified: 18 Jan 2023 21:00
DOI: 10.1073/pnas.2118510119
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3156385
Dimensions
Altmetric
CORE (COnnecting REpositories)