Lysolipids are prominent in subretinal drusenoid deposits, a high-risk phenotype in age-related macular degeneration.

Autor:	Anderson DMG; Department of Biochemistry, Vanderbilt University, Nashville TN., Kotnala A; Department of Biochemistry, Vanderbilt University, Nashville TN.; Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham AL., Migas LG; Delft Center for Systems and Control (DCSC), Delft University of Technology, Delft, Netherlands., Patterson NH; Department of Biochemistry, Vanderbilt University, Nashville TN., Tideman L; Delft Center for Systems and Control (DCSC), Delft University of Technology, Delft, Netherlands., Cao D; Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham AL., Adhikari B; Vision Science Graduate Program, University of Alabama at Birmingham, Birmingham AL., Messinger JD; Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham AL., Ach T; Department of Ophthalmology, University Hospital Bonn, Bonn, Germany., Tortorella S; Molecular Horizon Srl, Via Montelino 30, 06084 Bettona, Perugia, Italy., Van de Plas R; Department of Biochemistry, Vanderbilt University, Nashville TN.; Delft Center for Systems and Control (DCSC), Delft University of Technology, Delft, Netherlands., Curcio CA; Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham AL., Schey KL; Department of Biochemistry, Vanderbilt University, Nashville TN.
Jazyk:	angličtina
Zdroj:	Frontiers in ophthalmology [Front Ophthalmol (Lausanne)] 2023; Vol. 3. Date of Electronic Publication: 2023 Nov 24.
DOI:	10.3389/fopht.2023.1258734
Abstrakt:	Introduction: Age related macular degeneration (AMD) causes legal blindness worldwide, with few therapeutic targets in early disease and no treatments for 80% of cases. Extracellular deposits, including drusen and subretinal drusenoid deposits (SDD; also called reticular pseudodrusen), disrupt cone and rod photoreceptor functions and strongly confer risk for advanced disease. Due to the differential cholesterol composition of drusen and SDD, lipid transfer and cycling between photoreceptors and support cells are candidate dysregulated pathways leading to deposit formation. The current study explores this hypothesis through a comprehensive lipid compositional analysis of SDD. Methods: Histology and transmission electron microscopy were used to characterize the morphology of SDD. Highly sensitive tools of imaging mass spectrometry (IMS) and nano liquid chromatography tandem mass spectrometry (nLC-MS/MS) in positive and negative ion modes were used to spatially map and identify SDD lipids, respectively. An interpretable supervised machine learning approach was utilized to compare the lipid composition of SDD to regions of uninvolved retina across 1873 IMS features and to automatically discern candidate markers for SDD. Immunohistochemistry (IHC) was used to localize secretory phospholipase A2 group 5 (PLA2G5). Results: Among the 1873 detected features in IMS data, three lipid classes, including lysophosphatidylcholine (LysoPC), lysophosphatidylethanolamine (LysoPE) and lysophosphatidic acid (LysoPA) were observed nearly exclusively in SDD while presumed precursors, including phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidic acid (PA) lipids were detected in SDD and adjacent photoreceptor outer segments. Molecular signals specific to SDD were found in central retina and elsewhere. IHC results indicated abundant PLA2G5 in photoreceptors and retinal pigment epithelium (RPE). Discussion: The abundance of lysolipids in SDD implicates lipid remodeling or degradation in deposit formation, consistent with ultrastructural evidence of electron dense lipid-containing structures distinct from photoreceptor outer segment disks and immunolocalization of secretory PLA2G5 in photoreceptors and RPE. Further studies are required to understand the role of lipid signals observed in and around SDD. Competing Interests: TA has the following disclosures: Consultant for Roche, Novartis, Novartis, Bayer, Apellis Pharmaceutical Research support from Nidek outside this project. CC receives research funds from Genentech/Hoffman LaRoche and Heidelberg Engineering and consults for Apellis, Astellas, Boehringer Ingelheim, Character Biosciences, Osanni, and Annexon outside this project. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Databáze:	MEDLINE
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