Shinozaki, Youichi; Leung, Alex; Namekata, Kazuhiko; Saitoh, Sei; Nguyen, Huy Bang; Takeda, Akiko; Danjo, Yosuke; ... Koizumi, Schuichi; + view all 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; - view fewer (2022) Astrocytic dysfunction induced by ABCA1 deficiency causes optic neuropathy. Science Advances , 8 (44) , Article eabq1081. 10.1126/sciadv.abq1081.

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Abstract

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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