Lack of PNPLA2 accelerates progression of AMD-like features in mice

Authors

• J Yang
• A Bernardo-Colón
• SP Becerra

Abstract

Lipid accumulation in the retinal pigment epithelium (RPE) contributes to stress and progression of age-related macular degeneration (AMD). The role of Pnpla2, a gene involved in lipid regulation, in AMD development remains unclear. We investigated Pnpla2's impact on AMD progression.
Pnpla2 homozygous (Pnpla2-/-) (3 months) and heterozygous (Pnpla2+/-) (7 months) mice were used for RPE flatmounts and retinal cryosections. Senescence-associated-β-galactosidase (SA-β-gal) activity in situ, RPE nuclei counts, andimmunohistofluorescence ZO-1, phosphorylated H2AX (p-H2AX), and APOE were assessed. Fundus photography and electroretinography (ERG) were measured in Pnpla2+/- mice.
Pnpla2-/- RPE flatmounts showed increased SA-β-gal activity, and notable presence of multinucleated cells, comprising 73% of the population, indicative of cellular senescence. These RPE cells also displayed damaged tight junctions compared to wild type RPE. Increased numbers of p-H2AX -positive RPE cells (50%) were observed in Pnpla2-/- mice compared to wild type controls, suggesting heightened DNA damage. Additionally, preliminary results revealed elevated levels of APOE in Bruch’s membrane and subretinal regions of Pnpla2-/- mice relative to wild type mice. At 7 months of age, of Pnpla2+/- mice developed white spots, and the ERG c-wave amplitude was decreased compared to wild type mice.
Pnpla2 deficiency accelerates RPE aging and promotes geographic atrophy-like structures, a hallmark of AMD pathology. These findings underscore the potential role of PNPLA2 in mitigating the pathological progression of AMD and highlight its significance in retinal health and degeneration.

Scientific Focus Area: Molecular Biology and Biochemistry

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