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

Deborah A. Ferrington, Debasish Sinha, Kai Kaarniranta

Research output: Contribution to journalReview articlepeer-review

165 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)69-89
Number of pages21
JournalProgress in Retinal and Eye Research
StatePublished - Mar 1 2016

Bibliographical note

Funding Information:
DF is the recipient of the Elaine and Robert Larson Endowed Vision Research Chair. DS is a recipient of the Carolyn K. McGillvray Memorial Award for Macular Degeneration Research from BrightFocus Foundation and the Sybil B. Harrington Special Scholar Award for Macular Degeneration from Research to Prevent Blindness.

Funding Information:
The authors would like to acknowledge funding support from National Institutes of Health EY019037 (DS), EY019037-S (DS), The Finnish Eye Foundation (KK), The VTR grant ( 5503743 ) for Kuopio University Hospital (KK), Foundation Fighting Blindness ( 0613-0620-UMN , DF), Arnold and Mabel Beckman Initiative for Macular Research ( 1303 , DF), an anonymous benefactor for AMD Research (DF), Minnesota Lions Vision Foundation (DF), and unrestricted grants to the Department of Ophthalmology and Visual Neuroscience (U of MN) and the Wilmer Eye Institute from the Research to Prevent Blindness.

Publisher Copyright:
© 2015 Elsevier Ltd.


  • Age-related macular degeneration
  • Autophagy
  • Lysosome
  • Proteasome
  • Proteostasis
  • Retinal pigment epithelium


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