Bis(monoacylglycero)phosphate lipids in the retinal pigment epithelium implicate lysosomal/endosomal dysfunction in a model of Stargardt disease and human retinas
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Abstract Stargardt disease is a juvenile onset retinal degeneration, associated with elevated levels of lipofuscin and its bis-retinoid components, such as N-retinylidene-N-retinylethanolamine (A2E). However, the pathogenesis of Stargardt is still poorly understood and targeted treatments are not available. Utilizing high spatial and high mass resolution matrix assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS), we determined alterations of lipid profiles specifically localized to the retinal pigment epithelium (RPE) in Abca4 −/− Stargardt model mice compared to their relevant background strain. Extensive analysis by LC-MS/MS in both positive and negative ion mode was required to accurately confirm the identity of one highly expressed lipid class, bis(monoacylgylercoro)phosphate (BMP) lipids, and to distinguish them from isobaric species. The same BMP lipids were also detected in the RPE of healthy human retina. BMP lipids have been previously associated with the endosomal/lysosomal storage diseases Niemann-Pick and neuronal ceroid lipofuscinosis and have been reported to regulate cholesterol levels in endosomes. These results suggest that perturbations in lipid metabolism associated with late endosomal/lysosomal dysfunction may play a role in the pathogenesis of Stargardt disease and is evidenced in human retinas.
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Cholesterol-induced BMP accumulation is a characteristic feature of Abca4−/− RPE.
“This cholesterol-induced BMP accumulation is a characteristic feature of Abca4−/− RPE, first reported by immunostaining (Toops et al., 2015) and later confirmed by imaging mass spectrometry (Anderson et al., 2017).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Anderson et al., 2017
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- Authors
- Anderson, D. M. G., Ablonczy, Z., Koutalos, Y., Hanneken, A. M., Spraggins, J. M., Calcutt, M. W., Crouch, R. K., Caprioli, R. M., & Schey, K. L.
- Affiliations
- Vanderbilt University (US)
- Medical University of South Carolina (US)
- Scripps Research Institute (US)
- Corresponding author
- Schey, Kevin L.
- ORCID
- Venue
- Scientific Reports
- Published
- 2017-12-11
- Volume
- 7
- Issue
- 1
- Pages
- 17352-17352
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5725462
- OpenAlex
- W2772060643
- Cited by
- 48
- References
- 72
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 7 · 2018: 6
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Research to Prevent Blindness
- Medical University of South Carolina
- University of South Carolina
- National Institutes of Health (1c06rr015455-01a1, 1s10od012359-01, GM103391)
- National Eye Institute (R01EY019065, R01EY014850)
- National Institute of General Medical Sciences (P41GM103391)
- National Center for Research Resources (C06 RR-015455)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Keywords
- Stargardt disease, retinal pigment epithelium, lysosomal dysfunction, endosomal dysfunction, lipofuscin, A2E, retinal degeneration, lipid metabolism, MALDI mass spectrometry imaging, human retina
- MeSH terms
- Stargardt Disease, Animals, Disease Models, Animal, Humans, Lipids, Lysophospholipids, Lysosomes, Macular Degeneration, Endosomes, Retina, Mice, Knockout, ATP-Binding Cassette Transporters, Monoglycerides, Mice, Retinal Pigment Epithelium
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