Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy

• Published in: Science advances Vol. 8; no. 44
• Main Authors: Shinozaki, Youichi, Leung, Alex, Namekata, Kazuhiko, Saitoh, Sei, Nguyen, Huy Bang, Takeda, Akiko, Danjo, Yosuke, Morizawa, Yosuke M., Shigetomi, Eiji, Sano, Fumikazu, Yoshioka, Nozomu, Takebayashi, Hirohide, Ohno, Nobuhiko, Segawa, Takahiro, Miyake, Kunio, Kashiwagi, Kenji, Harada, Takayuki, Ohnuma, Shin-ichi, Koizumi, Schuichi
• Format: Journal Article
• Language: English
• Published: 04.11.2022
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abq1081

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. ABCA1 deficiency in retinal astrocytes causes normal-tension glaucoma-like phenotype in mice.