Bis(monoacylglycero)phosphate lipids in the retinal pigment epithelium implicate lysosomal/endosomal dysfunction in a model of Stargardt disease and human retinas

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.

Light‐responsive microRNA miR‐211 targets Ezrin to modulate lysosomal biogenesis and retinal cell clearance

“…Moreover, diurnal autophagy in the RPE ensures proficiency to deal with intracellular insults that occur from damaged mitochondria (Yao et al , ). Importantly, diurnal cargo degradation of both phagosomes and autophagosomes is critically sensitive to lysosomal biogenesis and variations in the normal levels of lysosomal proteins appear to result in a variety of retinal diseases (Frost et al , ; Ferrington et al , ; Tan et al , ; Anderson et al , ). In addition, defects in lysosomal function in the RPE have been considered to be key drivers of disease leading to conditions such as Stargardt's disease (Tan et al , ; Anderson et al , ) and age‐related macular degeneration (AMD) (Wang et al , ; Ferrington et al , ), the most common cause of blindness worldwide.…”

“…Importantly, diurnal cargo degradation of both phagosomes and autophagosomes is critically sensitive to lysosomal biogenesis and variations in the normal levels of lysosomal proteins appear to result in a variety of retinal diseases (Frost et al , ; Ferrington et al , ; Tan et al , ; Anderson et al , ). In addition, defects in lysosomal function in the RPE have been considered to be key drivers of disease leading to conditions such as Stargardt's disease (Tan et al , ; Anderson et al , ) and age‐related macular degeneration (AMD) (Wang et al , ; Ferrington et al , ), the most common cause of blindness worldwide. RPE/retina cells with diminished degradative processes are highly sensitive to the accumulation of toxic debris that can be deleterious for a large set of retinal cell lifespan in human eye diseases (Frost et al , ; Sethna et al , ; Sinha et al , ).…”

Oxidative Stress and Dysfunctional Intracellular Traffic Linked to an Unhealthy Diet Results in Impaired Cargo Transport in the Retinal Pigment Epithelium (RPE)

“…The daily internalization and proteolytic processing of photoreceptor outer segments (POS) from overlying photoreceptors as part of the visual cycle is a major function of the RPE. The accumulation of partially degraded POS as lipofuscin and its photo‐oxidative derivatives in the senescent RPE is a key feature of diseases including AMD and Stargardt disease . These lipid/protein aggregates accumulate within RPE lysosomes and related organelles such that approximately 20% of the cell cytosol may be filled with such material by the eighth decade of life .…”

Detection of small molecule concentration gradients in ocular tissues and humours

“…Proteins, peptides, lipids, and metabolites have been studied in the ocular lens of a range of species to understand the effects of ageing on the lens and implications for lens cataract formation. In the retina, both layer analysis via lipid detection and surface analysis of retinal flat mounts using metabolite detection have been studied to investigate some of the mechanisms involved in macular degeneration . Analysis of the whole eye has also been demonstrated for lipids, oligonucleotides, and used to trace drug penetration and movement in the eye .…”