Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration.

Ferrington, Deborah A.; Sinha, Debasish; Kaarniranta, Kai

doi:10.1016/j.preteyeres.2015.09.002

Cited by 241Retinal Diseases and TreatmentsAutophagy in Disease and TherapyRetinal Development and Disorders

Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration.

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Ferrington, Deborah A., Sinha, Debasish, Kaarniranta, Kai·2016·Progress in Retinal and Eye Research

DOI 10.1016/j.preteyeres.2015.09.002PMC PMC4769684

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Abstract

Maintenance of protein homeostasis, also referred to as "Proteostasis", integrates multiple pathways that regulate protein synthesis, folding, translocation, and degradation. Failure in proteostasis may be one of the underlying mechanisms responsible for the cascade of events leading to age-related macular degeneration (AMD). This review covers the major degradative pathways (ubiquitin-proteasome and lysosomal involvement in phagocytosis and autophagy) in the retinal pigment epithelium (RPE) and summarizes evidence of their involvement in AMD. Degradation of damaged and misfolded proteins via the proteasome occurs in coordination with heat shock proteins. Evidence of increased content of proteasome and heat shock proteins in retinas from human donors with AMD is consistent with increased oxidative stress and extensive protein damage with AMD. Phagocytosis and autophagy share key molecules in phagosome maturation as well as degradation of their cargo following fusion with lysosomes. Phagocytosis and degradation of photoreceptor outer segments ensures functional integrity of the neural retina. Autophagy rids the cell of toxic protein aggregates and defective mitochondria. Evidence suggesting a decline in autophagic flux includes the accumulation of autophagic substrates and damaged mitochondria in RPE from AMD donors. An age-related decrease in lysosomal enzymatic activity inhibits autophagic clearance of outer segments, mitochondria, and protein aggregates, thereby accelerating the accumulation of lipofuscin. This cumulative damage over a person's lifetime tips the balance in RPE from a state of para-inflammation, which strives to restore cell homeostasis, to the chronic inflammation associated with AMD.

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The RPE relies on LC3 for organelle-associated autophagy to maintain mitochondrial and peroxisomal health.
“The RPE relies on LC3 for (1) organelle associated autophagy to maintain mitochondrial and peroxisomal health (Ferrington et al., 2016)”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Ferrington et al., 2016
The RPE utilizes LC3 in LAP to decorate the outer membrane of phagosomes and in mitophagy and pexophagy to remove defective mitochondria and peroxisomes.
“The RPE utilizes LC3 in both processes; in LAP to decorate the outer membrane of phagosomes and in mitophagy and pexophagy to remove defective mitochondria and peroxisomes, respectively (Ferrington et al., 2016).”
From Microtubule-associated protein 1 light chain 3B, (LC3B) is necessary to maintain lipid-mediated homeostasis in the retinal pigment epithelium (2018) · cites this paper as Ferrington et al., 2016

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Investigating Mitochondria as a Target for Treating Age-Related Macular Degeneration
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Oxidative stress, polyunsaturated fatty acidsderived oxidation products and bisretinoids as potential inducers of CNS diseases: focus on age-related macular degeneration
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Authors: Ferrington, D. A., Sinha, D., & Kaarniranta, K.
Affiliations: University of Minnesota (US)
Johns Hopkins University (US)
University of Eastern Finland (FI)
Corresponding author: Ferrington, Deborah A.
ORCID: Ferrington, Deborah A.
Sinha, Debasish
Kaarniranta, Kai
Venue: Progress in Retinal and Eye Research
Publisher: Elsevier BV
Published: 2016-03
Volume: 51
Pages: 69-89
ISSN: 1350-9462 (ISSN-L)
DOI: 10.1016/j.preteyeres.2015.09.002
PMC: PMC4769684
OpenAlex: W1438640379
Cited by: 241
References: 197
Citations by year: 2026: 13 · 2025: 19 · 2024: 19 · 2023: 22 · 2022: 30 · 2021: 26 · 2020: 37 · 2019: 20 · 2018: 24 · 2017: 15 · 2016: 14 · 2015: 2
FWCI: 3.40
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Progress in Retinal and Eye Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (EY019037, EY019037-S)
The Finnish Eye Foundation
The VTR grant (5503743)
Foundation Fighting Blindness (0613-0620-UMN)
Arnold and Mabel Beckman Initiative for Macular Research (1303)
Topics: Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Keywords: age-related macular degeneration, retinal pigment epithelium, proteostasis, protein degradation, ubiquitin-proteasome system, lysosomal degradation, phagocytosis, autophagy, heat shock proteins, oxidative stress, photoreceptor outer segment phagocytosis, mitochondrial damage, lipofuscin accumulation, chronic inflammation, protein aggregates
MeSH terms: Animals, Autophagy, Humans, Lysosomes, Macular Degeneration, Phagocytosis, Ubiquitin-Protein Ligase Complexes, Proteasome Endopeptidase Complex, Retinal Pigment Epithelium, Proteolysis

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Defects in retinal pigment epithelial cell proteolysis and the pathology associated with age-related macular degeneration.

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