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

David M G Anderson, Ankita Kotnala, Lukasz G. Migas, N. Heath Patterson, Léonore E.M. Tideman, Thomas Ach, Sara Tortorella, Raf Van de Plas, Christine A. Curcio, Kevin L. Schey*, More Authors

*Corresponding author for this work

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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.

Original languageEnglish
Article number1258734
Number of pages18
JournalFrontiers in Ophthalmology
Volume3
DOIs
Publication statusPublished - 2023

Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by a Research to Prevent Blindness Catalyst Award (KS, CC, and RV) and by the National Institutes of Health (NIH) Common Fund, National Eye Institute, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Office of The Director (OD) under Award Numbers U54EY032442 (KS) and U54DK134302 (RV), R01EY027948, and R01EY015220. Acquisition of human tissues was supported in part by IZKF Würzburg (N-304, TA). The research was furthermore made possible in part by grant numbers 2021-240339 and 2022-309518 (LM and RV) from the Chan Zuckerberg Initiative DAF, an advised fund of Silicon Valley Community Foundation.

Keywords

  • age-related macular degeneration
  • imaging mass spectrometry
  • interpretable supervised machine learning
  • lysolipid
  • retinal pigment epithelium
  • SHAP maps
  • subretinal drusenoid deposit

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