Effect of selectively knocking down key metabolic genes in Müller glia on photoreceptor health
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- Weiyong Shen
- Discipline of Ophthalmology Sydney Medical School, The University of Sydney, Save Sight Institute Sydney New South Wales Australia
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- So‐Ra Lee
- Discipline of Ophthalmology Sydney Medical School, The University of Sydney, Save Sight Institute Sydney New South Wales Australia
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- Ashish Easow Mathai
- Discipline of Ophthalmology Sydney Medical School, The University of Sydney, Save Sight Institute Sydney New South Wales Australia
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- Rui Zhang
- Discipline of Ophthalmology Sydney Medical School, The University of Sydney, Save Sight Institute Sydney New South Wales Australia
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- Jianhai Du
- Department of Ophthalmology and Biochemistry West Virginia University Morgantown West Virginia USA
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- Michelle X. Yam
- Discipline of Ophthalmology Sydney Medical School, The University of Sydney, Save Sight Institute Sydney New South Wales Australia
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- Victoria Pye
- Discipline of Ophthalmology Sydney Medical School, The University of Sydney, Save Sight Institute Sydney New South Wales Australia
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- Nigel L. Barnett
- Clem Jones Centre for Regenerative Medicine, Faculty of Health Science & Medicine Bond University Gold Coast Queensland Australia
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- Cassie L. Rayner
- Clem Jones Centre for Regenerative Medicine, Faculty of Health Science & Medicine Bond University Gold Coast Queensland Australia
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- Ling Zhu
- Discipline of Ophthalmology Sydney Medical School, The University of Sydney, Save Sight Institute Sydney New South Wales Australia
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- James B. Hurley
- Department of Biochemistry University of Washington Seattle Washington USA
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- Pankaj Seth
- Division of Interdisciplinary Medicine Beth Israel Deaconess Medical Center and Harvard Medical School Boston Massachusetts USA
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- Yoshio Hirabayashi
- Sako Cellular Informatics Laboratory RIKEN Cluster for Pioneering Research Wako Japan
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- Shigeki Furuya
- Department of Bioscience and Biotechnology Kyushu University Fukuoka Japan
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- Mark C. Gillies
- Discipline of Ophthalmology Sydney Medical School, The University of Sydney, Save Sight Institute Sydney New South Wales Australia
説明
<jats:title>Abstract</jats:title><jats:p>The importance of Müller glia for retinal homeostasis suggests that they may have vulnerabilities that lead to retinal disease. Here, we studied the effect of selectively knocking down key metabolic genes in Müller glia on photoreceptor health. Immunostaining indicated that murine Müller glia expressed insulin receptor (IR), hexokinase 2 (HK2) and phosphoglycerate dehydrogenase (PHGDH) but very little pyruvate dehydrogenase E1 alpha 1 (PDH‐E1α) and lactate dehydrogenase A (LDH‐A). We crossed Müller glial cell‐CreER (MC‐CreER) mice with transgenic mice carrying a floxed IR, HK2, PDH‐E1α, LDH‐A, or PHGDH gene to study the effect of selectively knocking down key metabolic genes in Müller glia cells on retinal health. Selectively knocking down IR, HK2, or PHGDH led to photoreceptor degeneration and reduced electroretinographic responses. Supplementing exogenous <jats:sc>l</jats:sc>‐serine prevented photoreceptor degeneration and improved retinal function in MC‐PHGDH knockdown mice. We unexpectedly found that the levels of retinal serine and glycine were not reduced but, on the contrary, highly increased in MC‐PHGDH knockdown mice. Moreover, dietary serine supplementation, while rescuing the retinal phenotypes caused by genetic deletion of PHGDH in Müller glial cells, restored retinal serine and glycine homeostasis probably through regulation of serine transport. No retinal abnormalities were observed in MC‐CreER mice crossed with PDH‐E1α‐ or LDH‐A‐floxed mice despite Cre expression. Our findings suggest that Müller glia do not complete glycolysis but use glucose to produce serine to support photoreceptors. Supplementation with exogenous serine is effective in preventing photoreceptor degeneration caused by PHGDH deficiency in Müller glia.</jats:p>
収録刊行物
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- Glia
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Glia 69 (8), 1966-1986, 2021-04-09
Wiley
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詳細情報 詳細情報について
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- CRID
- 1360009142452123392
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- ISSN
- 10981136
- 08941491
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- データソース種別
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- Crossref
- KAKEN