Deletion of TSPO Causes Dysregulation of Cholesterol Metabolism in Mouse Retina.

Fahad Farhan,Aileen Wong,Xinhua Shu,Mohammad Almarhoun,Toby W Hurd,Chris Bartholomew,Amy S Findlay,Mark T S Williams

doi:10.3390/cells10113066

Abstract

Cholesterol dysregulation has been implicated in age-related macular degeneration (AMD), the most common cause of visual impairment in the elderly. The 18 KDa translocator protein (TSPO) is a mitochondrial outer membrane protein responsible for transporting cholesterol from the mitochondrial outer membrane to the inner membrane. TSPO is highly expressed in retinal pigment epithelial (RPE) cells, and TSPO ligands have shown therapeutic potential for the treatment of AMD. Here, we characterized retinal pathology of Tspo knockout (KO) mice using histological, immunohistochemical, biochemical and molecular biological approaches. We found that Tspo KO mice had normal retinal morphology (by light microscopy) but showed elevated levels of cholesterol, triglycerides and phospholipids with perturbed cholesterol efflux in the RPE cells of Tspo KO mice. Expression of cholesterol-associated genes (Nr1h3, Abca1, Abcg1, Cyp27a1 and Cyp46a1) was significantly downregulated, and production of pro-inflammatory cytokines was markedly increased in Tspo KO retinas. Furthermore, microglial activation was also observed in Tspo KO mouse retinas. These findings provide new insights into the function of TSPO in the retina and may aid in the design of new therapeutic strategies for the treatment of AMD.

Highlights

Published: 7 November 2021Age-related macular degeneration (AMD) is the most frequent condition leading to legally defined blindness among senior citizens
We found that wildtype for (WT) mouse retinal pigment epithelial (RPE)/choroid/sclera expressed high levels of translocator protein (TSPO) protein, with lower levels found in the neural retinas (Figures S1B and S2A), consistent with our previous report [18]
It is possible that low levels of TSPO protein in the whole brain lysates are undetectable by Western blot

Summary

Introduction

Age-related macular degeneration (AMD) is the most frequent condition leading to legally defined blindness among senior citizens. In early stages of the disease, AMD patients may encounter no or limited vision loss. As the disease progresses, they may experience the total loss of central vision, resulting in complete blindness. Patients may discern no significant disturbance to peripheral vision, but the condition can have an adverse effect on their ability to read or drive [1]. The disease is seldom detected in people under 50 years of age, but the prevalence rises with aging, with. 60% of people over the age of 90 affected by AMD [2,3]. Late AMD is divided into two subgroups: dry (geographic atrophy, accounting for 90% of AMD) and wet (neovascular)

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