Abstract
Glaucoma is a leading cause of blindness worldwide. Although an elevated intraocular pressure (IOP) is considered to damages retinal ganglion cells (RGCs) thereby causing blindness, it has become apparent that many risk factors other than IOP are involved in the etiology of glaucoma. Recent genome wide association studies (GWAS) have identified that single nucleotide polymorphism (SNP) of ABCA1 gene is the highest risk for glaucoma. However, its pathogenic mechanisms are totally unclear. To address this issue, we analyzed molecular mechanisms using conventional ABCA1 knockout (KO) mice. We found that deficiency of ABCA did not increase IOP levels regardless of their age. Importantly, ABCA1KO mice at middle-age (12 months old) showed significant increases in the number of apoptotic RGCs. We also found that ABCA1 was enriched in astrocytes. To further clarifying the role of astrocytic ABCA1, we generated astrocyte-specific ABCA1 knockout (cKO) mice. The cKO mice had no IOP elevation and increased the number of apoptotic RGCs. The cKO mice also showed impaired visual functions at middle-age. Taken together, our data showed that (1) ABCA1 has no impact on IOP; (2) loss-of-function of ABCA1 is involved in glaucoma; and (3) ABCA1 in glial cells contributes to pathogenesis of glaucoma.
