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

Journal article (2023)

Authors

David M G Anderson VanderBilt University
Ankita Kotnala VanderBilt University, University of Alabama at Birmingham
More Authors... External organisation
L.G. Migas Team Raf Van de Plas - Mechanical, Maritime and Materials Engineering
Nathan Heath Patterson VanderBilt University
L.E.M. Tideman Team Raf Van de Plas - Mechanical, Maritime and Materials Engineering
Thomas Ach Bonn University Hospital
Sara Tortorella Molecular Horizon Srl
Raf Van de Plas VanderBilt University, Team Raf Van de Plas - Mechanical, Maritime and Materials Engineering
Christine A. Curcio University of Alabama at Birmingham
Kevin L. Schey VanderBilt University
Research Group
Team Raf Van de Plas (Mechanical, Maritime and Materials Engineering) (TU Delft)
Copyright: © 2023 David M G Anderson, Ankita Kotnala, L.G. Migas, N. Heath Patterson, L.E.M. Tideman, Thomas Ach, Sara Tortorella, Raf Van de Plas, Christine A. Curcio, Kevin L. Schey, More Authors
DOI: https://doi.org/10.3389/fopht.2023.1258734
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Published Date

2023

Language

English

Faculty

Mechanical, Maritime and Materials Engineering

Department

Delft Center for Systems and Control

Research Group

Team Raf Van de Plas

Abstract

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.