Aberrant early endosome biogenesis mediates complement activation in the retinal pigment epithelium in models of macular degeneration
Open accessAbstract
Significance The first lines of communication between cells and the environment are early endosomes, which sort incoming cargo to regulate cell health. Endosomal abnormalities are seen in neurodegenerative diseases, yet the molecular mechanisms remain obscure. Here, using human donor cells and disease models, we demonstrate that excess ceramide promotes expansion of early endosomes in the retinal pigment epithelium (RPE), a primary site of injury in Stargardt and age-related maculopathies. Complement C3 uptake into enlarged endosomes and subsequent cleavage is associated with abnormal mechanistic target of rapamycin activity. Decreasing ceramide using Food and Drug Administration-approved drugs corrects endosomal defects and prevents C3 activation. Our studies establish how organelles modulate RPE complement activity, and identify ceramide as a drug target for macular degenerations.
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In Abca4−/− RPE and in RPE from aged human donors, lipofuscin bisretinoids drive ceramide accumulation on the apical plasma membrane, resulting in enlarged early endosomes that act as conduits for complement C3 entry.
“in Abca4−/− RPE and in RPE from aged human donors, lipofuscin bisretinoids drive the accumulation of ceramide - a cone-shaped lipid that promotes spontaneous negative curvature and inward budding - on the apical plasma membrane. This results in the formation of enlarged early endosomes from the apical surface, and these endosomes act as conduits for the entry of complement C3, as discussed above”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kaur et al., 2018
Abca4−/− Stargardt disease RPE exhibit a block in autophagosome biogenesis as a result of chronic mTOR activation driven by intracellular C3 cleavage.
“In contrast to these three diseases, which are characterized by an accumulation of autophagosomes, Abca4−/− Stargardt disease RPE exhibit a block in autophagosome biogenesis (Toops et al., 2015) as a result of chronic mTOR activation driven by intracellular C3 cleavage (Kaur et al., 2018) (Fig. 13).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kaur et al., 2018
Intracellular C3a is almost undetectable in healthy RPE, likely due to efficient recycling or degradation.
“Intracellular C3a is almost undetectable in healthy RPE, likely due to efficient recycling or degradation; on the other hand, increased uptake of C3 in Abca4−/− RPE from the extracellular milieu into enlarged early endosomes (discussed in detail below) enables the generation of intracellular C3a, and consequently, sustained activation of mTOR (Kaur et al., 2018).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kaur et al., 2018
Increased uptake of C3 in Abca4−/− RPE from the extracellular milieu into enlarged early endosomes enables the generation of intracellular C3a, and consequently sustained activation of mTOR.
“Intracellular C3a is almost undetectable in healthy RPE, likely due to efficient recycling or degradation; on the other hand, increased uptake of C3 in Abca4−/− RPE from the extracellular milieu into enlarged early endosomes (discussed in detail below) enables the generation of intracellular C3a, and consequently, sustained activation of mTOR (Kaur et al., 2018).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kaur et al., 2018
Studies have now established that this mechanism is also operational in the RPE.
“Studies have now established that this mechanism is also operational in the RPE.”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kaur et al., 2018
Circadian clearance of OS phagosomes by the RPE occurs normally in the Abca4−/− model, suggesting that cathepsin D activity is not affected.
“Circadian clearance of OS phagosomes by the RPE occurs normally in this model, suggesting that cathepsin D activity is not affected (Kaur et al., 2018).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Kaur et al., 2018
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The cell biology of the retinal pigment epithelium
Lakkaraju, A., Umapathy, A., Tan, L. X., Daniele, L., Philp, N. J., Boesze-Battaglia, K., & Williams, D. S. (2020) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2020.100846 · Cited by 422 · see citing works
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- Authors
- Kaur, G., Tan, L. X., Rathnasamy, G., La Cunza, N., Germer, C. J., Toops, K. A., Fernandes, M., Blenkinsop, T. A., & Lakkaraju, A.
- Affiliations
- University of Wisconsin–Madison (US)
- Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI 53706;
- Icahn School of Medicine at Mount Sinai (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-08-20
- Volume
- 115
- Issue
- 36
- Pages
- 9014-9019
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6130344
- OpenAlex
- W2888110702
- Cited by
- 79
- References
- 39
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 12 · 2023: 13 · 2022: 10 · 2021: 8 · 2020: 11 · 2019: 11
- FWCI
- 7.54
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- HHS | NIH | National Eye Institute (EY023299, P30EY016665)
- BrightFocus Foundation (M2015350)
- Carl Marshall and Mildred Almen Reeves Foundation (NA)
- Research to Prevent Blindness (NA)
- Macular Society UK (NA)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Keywords
- retinal pigment epithelium, complement activation, C3 cleavage, ceramide, age-related macular degeneration, mTOR signaling, therapeutic target
- MeSH terms
- Stargardt Disease, Aged, Aged, 80 and over, Animals, Ceramides, Disease Models, Animal, Female, Humans, Macular Degeneration, Male, Endosomes, Swine, Complement C3a, Mice, Knockout, ATP-Binding Cassette Transporters, Mice, Retinal Pigment Epithelium, TOR Serine-Threonine Kinases
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