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Cholesterol homeostasis regulated by ABCA1 is critical for retinal ganglion cell survival

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An Erratum to this article was published on 18 April 2024

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Abstract

Genome-wide association studies have suggested a link between primary open-angle glaucoma and the function of ABCA1. ABCA1 is a key regulator of cholesterol efflux and the biogenesis of high-density lipoprotein (HDL) particles. Here, we showed that the POAG risk allele near ABCA1 attenuated ABCA1 expression in cultured cells. Consistently, POAG patients exhibited lower ABCA1 expression, reduced HDL, and higher cholesterol in white blood cells. Ablation of Abca1 in mice failed to form HDL, leading to elevated cholesterol levels in the retina. Counting retinal ganglion cells (RGCs) by using an artificial intelligence (AI) program revealed that Abca1-deficient mice progressively lost RGCs with age. Single-cell RNA sequencing (scRNA-seq) revealed aberrant oxidative phosphorylation in the Abca1−/− retina, as well as activation of the mTORC1 signaling pathway and suppression of autophagy. Treatment of Abca1−/− mice using atorvastatin reduced the cholesterol level in the retina, thereby improving metabolism and protecting RGCs from death. Collectively, we show that lower ABCA1 expression and lower HDL are risk factors for POAG. Accumulated cholesterol in the Abca1−/− retina causes profound aberrant metabolism, leading to a POAG-like phenotype that can be prevented by atorvastatin. Our findings establish statin use as a preventive treatment for POAG associated with lower ABCA1 expression.

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References

  • Bailey, J.N.C., Loomis, S.J., Kang, J.H., Allingham, R.R., Gharahkhani, P., Khor, C.C., Burdon, K.P., Aschard, H., Chasman, D.I., Igo Jr, R.P., et al. (2016). Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet 48, 189–194.

    Article  PubMed  Google Scholar 

  • Björkhem, I., Lütjohann, D., Breuer, O., Sakinis, A., and Wennmalm, A. (1997). Importance of a novel oxidative mechanism for elimination of brain cholesterol. J Biol Chem 272, 30178–30184.

    Article  PubMed  Google Scholar 

  • Bodzioch, M., Orsó, E., Klucken, J., Langmann, T., Böttcher, A., Diederich, W., Drobnik, W., Barlage, S., Büchler, C., Porsch-Ozcürümez, M., et al. (1999). The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22, 347–351.

    Article  CAS  PubMed  Google Scholar 

  • Bretillon, L., Thuret, G., Grégoire, S., Acar, N., Joffre, C., Bron, A.M., Gain, P., and Creuzot-Garcher, C.P. (2008). Lipid and fatty acid profile of the retina, retinal pigment epithelium/choroid, and the lacrimal gland, and associations with adipose tissue fatty acids in human subjects. Exp Eye Res 87, 521–528.

    Article  CAS  PubMed  Google Scholar 

  • Brooks-Wilson, A., Marcil, M., Clee, S.M., Zhang, L.H., Roomp, K., van Dam, M., Yu, L., Brewer, C., Collins, J.A., Molhuizen, H.O.F., et al. (1999). Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet 22, 336–345.

    Article  CAS  PubMed  Google Scholar 

  • Burdon, K.P., Macgregor, S., Hewitt, A.W., Sharma, S., Chidlow, G., Mills, R.A., Danoy, P., Casson, R., Viswanathan, A.C., Liu, J.Z., et al. (2011). Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 43, 574–578.

    Article  CAS  PubMed  Google Scholar 

  • Carelli, V., La Morgia, C., Ross-Cisneros, F.N., and Sadun, A.A. (2017). Optic neuropathies: the tip of the neurodegeneration iceberg. Hum Mol Genet 26, R139–R150.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carelli, V., Ross-Cisneros, F.N., and Sadun, A.A. (2004). Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retinal Eye Res 23, 53–89.

    Article  CAS  Google Scholar 

  • Chen, J., Zhang, X., Kusumo, H., Costa, L.G., and Guizzetti, M. (2013). Cholesterol efflux is differentially regulated in neurons and astrocytes: implications for brain cholesterol homeostasis. Biochim Biophys Acta (BBA)-Mol Cell Biol Lipids 1831, 263–275.

    CAS  Google Scholar 

  • Chen, Y., Lin, Y., Vithana, E.N., Jia, L., Zuo, X., Wong, T.Y., Chen, L.J., Zhu, X., Tam, P.O.S., Gong, B., et al. (2014). Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma. Nat Genet 46, 1115–1119.

    Article  CAS  PubMed  Google Scholar 

  • Claudepierre, T., Paques, M., Simonutti, M., Buard, I., Sahel, J., Maue, R. A., Picaud, S., and Pfrieger, F.W. (2010). Lack of Niemann-Pick type C1 induces age-related degeneration in the mouse retina. Mol Cell Neurosci 43, 164–176.

    Article  CAS  PubMed  Google Scholar 

  • Fingert, J.H., Robin, A.L., Stone, J.L., Roos, B.R., Davis, L.K., Scheetz, T. E., Bennett, S.R., Wassink, T.H., Kwon, Y.H., Alward, W.L.M., et al. (2011). Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum Mol Genet 20, 2482–2494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fliesler, S.J., and Bretillon, L. (2010). The ins and outs of cholesterol in the vertebrate retina. J Lipid Res 51, 3399–3413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fliesler, S.J., Peachey, N.S., Richards, M.J., Nagel, B.A., and Vaughan, D. K. (2004). Retinal degeneration in a rodent model of Smith-Lemli-Opitz syndrome. Arch Ophthalmol 122, 1190–1200.

    Article  PubMed  PubMed Central  Google Scholar 

  • Footz, T.K., Johnson, J.L., Dubois, S., Boivin, N., Raymond, V., and Walter, M.A. (2009). Glaucoma-associated WDR36 variants encode functional defects in a yeast model system. Hum Mol Genet 18, 1276–1287.

    Article  CAS  PubMed  Google Scholar 

  • Fourgeux, C., Martine, L., Björkhem, I., Diczfalusy, U., Joffre, C., Acar, N., Creuzot-Garcher, C., Bron, A., and Bretillon, L. (2009). Primary open-angle glaucoma: association with cholesterol 24S-hydroxylase (CYP46A1) gene polymorphism and plasma 24-hydroxycholesterol levels. Invest Ophthalmol Vis Sci 50, 5712.

    Article  PubMed  Google Scholar 

  • Garry, D., Hansen, R.M., Moskowitz, A., Elias, E.R., Irons, M., and Fulton, A.B. (2010). Cone ERG responses in patients with Smith-Lemli-Opitz Syndrome (SLOS). Doc Ophthalmol 121, 85–91.

    Article  PubMed  PubMed Central  Google Scholar 

  • Gharahkhani, P., Burdon, K.P., Fogarty, R., Sharma, S., Hewitt, A.W., Martin, S., Law, M.H., Cremin, K., Bailey, J.N.C., Loomis, S.J., et al. (2014). Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nat Genet 46, 1120–1125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gong, B., Zhang, H., Huang, L., Chen, Y., Shi, Y., Tam, P.O.S., Zhu, X., Huang, Y., Lei, B., Sundaresan, P., et al. (2019). Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis. Genet Med 21, 2345–2354.

    Article  CAS  PubMed  Google Scholar 

  • Hamon, Y., Broccardo, C., Chambenoit, O., Luciani, M.F., Toti, F., Chaslin, S., Freyssinet, J.M., Devaux, P.F., McNeish, J., Marguet, D., et al. (2000). ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine. Nat Cell Biol 2, 399–406.

    Article  CAS  PubMed  Google Scholar 

  • Hysi, P.G., Cheng, C.Y., Springelkamp, H., Macgregor, S., Bailey, J.N.C., Wojciechowski, R., Vitart, V., Nag, A., Hewitt, A.W., Höhn, R., et al. (2014). Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma. Nat Genet 46, 1126–1130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ito, J., Nagayasu, Y., Miura, Y., Yokoyama, S., and Michikawa, M. (2014). Astrocyte’s endogenous apoE generates HDL-like lipoproteins using previously synthesized cholesterol through interaction with ABCA1. Brain Res 1570, 1–12.

    Article  CAS  PubMed  Google Scholar 

  • Ji, A., Wroblewski, J.M., Cai, L., de Beer, M.C., Webb, N.R., and van der Westhuyzen, D.R. (2012). Nascent HDL formation in hepatocytes and role of ABCA1, ABCG1, and SR-BI. J Lipid Res 53, 446–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koldamova, R., Staufenbiel, M., and Lefterov, I. (2005). Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 280, 43224–43235.

    Article  CAS  PubMed  Google Scholar 

  • Li, Z., Allingham, R.R., Nakano, M., Jia, L., Chen, Y., Ikeda, Y., Mani, B., Chen, L.J., Kee, C., Garway-Heath, D.F., et al. (2015). A common variant near TGFBR3 is associated with primary open angle glaucoma. Hum Mol Genet 24, 3880–3892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., Vera, D. L., Zeng, Q., Yu, D., Bonkowski, M.S., et al. (2020). Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marcus, M.W., Müskens, R.P.H.M., Ramdas, W.D., Wolfs, R.C.W., De Jong, P.T.V.M., Vingerling, J.R., Hofman, A., Stricker, B.H., and Jansonius, N.M. (2012). Cholesterol-lowering drugs and incident open-angle glaucoma: a population-based cohort study. PLoS ONE 7, e29724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McGwin, G. Jr., McNeal, S., Owsley, C., Girkin, C., Epstein, D., and Lee, P.P. (2004). Statins and other cholesterol-lowering medications and the presenceof glaucoma. Arch Ophthalmol 122, 822–826.

    Article  CAS  PubMed  Google Scholar 

  • Owen, C.G., Carey, I.M., Shah, S., de Wilde, S., Wormald, R., Whincup, P. H., and Cook, D.G. (2010). Hypotensive medication, statins, and the risk of glaucoma. Invest Ophthalmol Vis Sci 51, 3524–3530.

    Article  PubMed  Google Scholar 

  • Pasutto, F., Keller, K.E., Weisschuh, N., Sticht, H., Samples, J.R., Yang, Y. F., Zenkel, M., Schlötzer-Schrehardt, U., Mardin, C.Y., Frezzotti, P., et al. (2012). Variants in ASB10 are associated with open-angle glaucoma. Hum Mol Genet 21, 1336–1349.

    Article  CAS  PubMed  Google Scholar 

  • Rezaie, T., Child, A., Hitchings, R., Brice, G., Miller, L., Coca-Prados, M., Heon, E., Krupin, T., Ritch, R., Kreutzer, D., et al. (2002). Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295, 1077–1079.

    Article  CAS  PubMed  Google Scholar 

  • Rust, S., Rosier, M., Funke, H., Real, J., Amoura, Z., Piette, J.C., Deleuze, J.F., Brewer, H.B., Duverger, N., Denèfle, P., et al. (1999). Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22, 352–355.

    Article  CAS  PubMed  Google Scholar 

  • Springelkamp, H., Iglesias, A.I., Cuellar-Partida, G., Amin, N., Burdon, K. P., van Leeuwen, E.M., Gharahkhani, P., Mishra, A., van der Lee, S.J., Hewitt, A.W., et al. (2015). ARHGEF12 influences the risk of glaucoma by increasing intraocular pressure. Hum Mol Genet 24, 2689–2699.

    Article  CAS  PubMed  Google Scholar 

  • Stone, E.M., Fingert, J.H., Alward, W.L.M., Nguyen, T.D., Polansky, J.R., Sunden, S.L.F., Nishimura, D., Clark, A.F., Nystuen, A., Nichols, B.E., et al. (1997). Identification of a gene that causes primary open angle glaucoma. Science 275, 668–670.

    Article  CAS  PubMed  Google Scholar 

  • Tham, Y.C., Li, X., Wong, T.Y., Quigley, H.A., Aung, T., and Cheng, C.Y. (2014). Global prevalence of glaucoma and projections of glaucoma burden through 2040. Ophthalmology 121, 2081–2090.

    Article  PubMed  Google Scholar 

  • Thorleifsson, G., Walters, G.B., Hewitt, A.W., Masson, G., Helgason, A., DeWan, A., Sigurdsson, A., Jonasdottir, A., Gudjonsson, S.A., Magnusson, K.P., et al. (2010). Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 42, 906–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tyagi, N., Tyagi, M., Pachauri, M., and Ghosh, P.C. (2015). Potential therapeutic applications of plant toxin-ricin in cancer: challenges and advances. Tumor Biol 36, 8239–8246.

    Article  CAS  Google Scholar 

  • Wahrle, S.E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., Jain, S., Hirsch-Reinshagen, V., Wellington, C.L., Bales, K.R., et al. (2008). Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118, 671–682.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, S., and Bao, X. (2019). Hyperlipidemia, blood lipid level, and the risk of glaucoma: a meta-analysis. Invest Ophthalmol Vis Sci 60, 1028–1043.

    Article  PubMed  Google Scholar 

  • Wiggs, J.L., Yaspan, B.L., Hauser, M.A., Kang, J.H., Allingham, R.R., Olson, L.M., Abdrabou, W., Fan, B.J., Wang, D.Y., Brodeur, W., et al. (2012). Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 8, e1002654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Williams, P.A., Harder, J.M., Foxworth, N.E., Cochran, K.E., Philip, V.M., Porciatti, V., Smithies, O., and John, S.W.M. (2017). Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice. Science 355, 756–760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ye, X., Wang, Y., and Nathans, J. (2010). The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends Mol Med 16, 417–425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zyss, J., Béhin, A., Couvert, P., Bouhour, F., Sassolas, A., Kolev, I., Denys, V., Vial, C., Lacour, A., Carrié, A., et al. (2012). Clinical and electrophysiological characteristics of neuropathy associated with Tangier disease. J Neurol 259, 1222–1226.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Precision Medicine Project (2016YFC0905200), the National Natural Science Foundation of China (81790643, 82121003, 81570882, 81770935, 81670853, 81271005), the grant from Chinese Academy of Medical Sciences (2019-I2M-5-032), and the grant from the Department of Science and Technology of Sichuan Province (2021YFS0404, 2021FS0369, 2020YJ0445, 2019JDJQ0031, 2022JDTD0024). We thank all the patients with POAG and their families for participating in this study.

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Authors and Affiliations

  1. Key Laboratory for Human Disease Gene Study of Sichuan Province and Institute of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China

    Jialiang Yang, Tongdan Zou, Bai Xue, Fang Yang, Yuxia Xu, Shiyu He, Xiong Zhu, Lin Zhang, Yu Zhou, Zhengfu Tai, Ping Shuai, Bo Gong, Xianjun Zhu, Ying Lin, Houbin Zhang & Zhenglin Yang

  2. Department of Ophthalmology and Visual Science, Eye and Ear Nose Throat (ENT) Hospital, Fudan University, Shanghai, 200032, China

    Yuhong Chen & Xinghuai Sun

  3. School of Optoelectronic Science and Engineering, University of Electronic Science and Technology of China, Chengdu, 611731, China

    Xiangzhou Wang, Yibo Huo, Boyun Yan & Jing Zhang

  4. Institute of Chengdu Biology, Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, 610093, China

    Yi Yin, Jing Wang & Zhenglin Yang

  5. Department of Ophthalmology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China

    Man Yu, Qian Luo & Yilian Cheng

  6. Research Unit for Blindness Prevention of Chinese Academy of Medical Sciences, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, 610072, China

    Bo Gong, Xianjun Zhu & Zhenglin Yang

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  1. Jialiang Yang
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  2. Yuhong Chen
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  3. Tongdan Zou
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  9. Yuxia Xu
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Correspondence to Houbin Zhang or Zhenglin Yang.

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Compliance and ethics The author(s) declare that they have no conflict of interest. This study was performed in accordance with the principles of the Helsinki Declaration of the World Medical Association. The protocol was approved by the Institutional Ethics Committee of Sichuan Provincial People’s Hospital.

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Yang, J., Chen, Y., Zou, T. et al. Cholesterol homeostasis regulated by ABCA1 is critical for retinal ganglion cell survival. Sci. China Life Sci. 66, 211–225 (2023). https://doi.org/10.1007/s11427-021-2126-2

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