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Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy.

Youichi ShinozakiAlex LeungKazuhiko NamekataSei SaitohHuy Bang NguyenAkiko TakedaYosuke DanjoYosuke M MorizawaEiji ShigetomiFumikazu SanoNozomu YoshiokaHirohide TakebayashiNobuhiko OhnoTakahiro SegawaKunio MiyakeKenji KashiwagiTakayuki HaradaShin-Ichi OhnumaSchuichi Koizumi
Published in: Science advances (2022)
Astrocyte abnormalities have received great attention for their association with various diseases in the brain but not so much in the eye. Recent independent genome-wide association studies of glaucoma, optic neuropathy characterized by retinal ganglion cell (RGC) degeneration, and vision loss found that single-nucleotide polymorphisms near the ABCA1 locus were common risk factors. Here, we show that Abca1 loss in retinal astrocytes causes glaucoma-like optic neuropathy in aged mice. ABCA1 was highly expressed in retinal astrocytes in mice. Thus, we generated macroglia-specific Abca1 -deficient mice (Glia-KO) and found that aged Glia-KO mice had RGC degeneration and ocular dysfunction without affected intraocular pressure, a conventional risk factor for glaucoma. Single-cell RNA sequencing revealed that Abca1 deficiency in aged Glia-KO mice caused astrocyte-triggered inflammation and increased the susceptibility of certain RGC clusters to excitotoxicity. Together, astrocytes play a pivotal role in eye diseases, and loss of ABCA1 in astrocytes causes glaucoma-like neuropathy.
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