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Disrupted Blood-Retina Lysophosphatidylcholine Transport Research Articles: Cellular/Molecular Disrupted blood-retina lysophosphatidylcholine transport impairs photoreceptor health but not visual signal transduction https://doi.org/10.1523/JNEUROSCI.1142-19.2019 Cite as: J. Neurosci 2019; 10.1523/JNEUROSCI.1142-19.2019 Received: 16 May 2019 Revised: 4 October 2019 Accepted: 23 October 2019 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2019 the authors 1 Disrupted blood-retina lysophosphatidylcholine transport impairs 2 photoreceptor health but not visual signal transduction 3 4 Abbreviated title (50 characters): Photoreceptor function under DHA deprivation 5 6 Ekaterina S. Lobanova1,2*, Kai Schuhmann3, Stella Finkelstein4, Tylor R. Lewis4, Martha 7 A. Cady4, Ying Hao4, Casey Keuthan1,5, John D. Ash1,5, Marie E. Burns6, Andrej 8 Shevchenko3, and Vadim Y. Arshavsky4,7* 9 1Department of Ophthalmology, University of Florida, Gainesville, FL, 32610 10 2Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610 11 3Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, 01307 12 4Department of Ophthalmology, Duke University, Durham, NC, 27710 13 5Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, 14 32610 15 6Department of Cell Biology and Human Anatomy, University of California-Davis, Davis, CA, 16 95618 17 7Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 27710 18 19 Send correspondence to Ekaterina Lobanova at [email protected] or Vadim Arshavsky at 20 [email protected]. 21 22 The manuscript contains 29 pages, 1 table, 11 figures, 3 extended figures (Excel spreadsheets). 23 24 The abstract contains 246 words, Introduction – 558 words, Discussion – 1,498 words 25 26 The authors declare no competing financial interests 27 Acknowledgments: The authors are grateful to Dr. David L Silver (Duke NUS) for many 28 helpful discussions and critical reading of the manuscript. This work was supported by the Duke 29 NUS Pilot Award “The role of DHA in supporting retinal function” (V.Y.A.); the National 30 Institutes of Health grants EY022959 (V.Y.A.), EY05722 (V.Y.A.), EY016459 (J.D.A.), 31 EY014047 (M.E.B.), and EY030043(E.S.L), a grant from the Knights Templar Eye Foundation 32 (E.S.L.), The University of Florida startup funds (E.S.L.), unrestricted grants from Research to 33 Prevent Blindness to the Departments of Ophthalmology of University of Florida and Duke 34 University, the German Research Foundation TRR83 grant project A17 (A.S.) and Federal 35 Ministry of Education and Research LIFS grant (A.S.). 1 36 Abstract 37 Retinal photoreceptor cells contain the highest concentration of docosahexaenoic acid (DHA) in 38 our bodies, and it has been long assumed that this is critical for supporting normal vision. Indeed, 39 early studies employing DHA dietary restriction documented reduced light sensitivity by DHA- 40 deprived retinas. Recently, it has been demonstrated that a major route of DHA entry in the 41 retina is the delivery across the blood-retina barrier by the sodium-dependent lipid transporter, 42 Mfsd2a. This discovery opened a unique opportunity to analyze photoreceptor health and 43 function in DHA-deprived retinas using the Mfsd2a knockout mouse as animal model. Our 44 lipidome analyses of Mfsd2a-/- retinas and outer segment membranes corroborated the previously 45 reported decrease in the fraction of DHA-containing phospholipids and a compensatory increase 46 in phospholipids containing arachidonic acid. We also revealed an increase in the retinal content 47 of monounsaturated fatty acids and a reduction in very long chain fatty acids. These changes 48 could be explained by a combination of reduced DHA supply to the retina and a concomitant 49 upregulation of several fatty acid desaturases controlled by sterol regulatory element-binding 50 transcription factors, which are upregulated in Mfsd2a-/- retinas. Mfsd2a-/- retinas undergo slow 51 progressive degeneration, with ~30% of photoreceptor cells lost by the age of 6 months. Despite 52 this pathology, the ultrastructure Mfsd2a-/- photoreceptors and their ability to produce light 53 responses were essentially normal. These data demonstrate that, whereas maintaining the LPC 54 route of DHA supply to the retina is essential for long-term photoreceptor survival, it is not 55 important for supporting normal phototransduction. 56 Significance statement (120 words) 2 57 Phospholipids containing docosahexaenoic acid (DHA) are greatly enriched in the nervous 58 system, with the highest concentration found in the light-sensitive membranes of photoreceptor 59 cells. In this study, we analyzed the consequences of impaired DHA transport across the blood- 60 retina barrier. We have found that, in addition to a predictable reduction in the DHA level, the 61 affected retinas undergo a complex, transcriptionally-driven rebuilding of their membrane 62 lipidome in a pattern preserving the overall saturation/desaturation balance of retinal 63 phospholipids. Remarkably, these changes do not affect the ability of photoreceptors to produce 64 responses to light but are detrimental for the long-term survival of these cells. 3 65 Introduction 66 There is ample evidence supporting the health benefits of consuming omega-3 fats, i.e. 67 phospholipids containing docosahexaenoic acid (DHA) moieties. DHA is highly concentrated in 68 the nervous system despite the fact that DHA cannot be synthetized by neurons and has to be 69 transported to the brain across the blood-brain barrier (BBB). A major breakthrough in 70 understanding this transport was reported by Silver and colleagues (Nguyen et al., 2014) who 71 discovered that facilitative transporter Mfsd2a, expressed in the endothelium of the BBB micro- 72 vessels, is responsible for the uptake of plasma lysophosphatidylcholines (LPCs) across the 73 BBB, thereby serving as a primary mechanism of DHA delivery to the brain. Mfsd2a knockout, 74 as well as its mutations, results in microcephaly and hypomyelination in animal models and 75 human patients (Nguyen et al., 2014; Alakbarzade et al., 2015; Guemez-Gamboa et al., 2015; 76 Chan et al., 2018; Harel et al., 2018). 77 Remarkably, the retina contains even more DHA than the brain, with the highest 78 concentration found in the light-sensitive outer segment membranes of rod and cone 79 photoreceptor cells (Fliesler and Anderson, 1983). It is generally agreed that, like the brain, the 80 retina cannot synthesize its own DHA de novo and relies on uptake from extraretinal sources, 81 such as bloodborne lipids, for maintaining its DHA content (e.g. (Scott and Bazan, 1989; Bazan 82 et al., 2011)). Multiple studies analyzing the consequences of DHA dietary restriction 83 documented that DHA-deprived retinas produced light responses of reduced sensitivity 84 (Benolken et al., 1973; Wheeler et al., 1975; Senapati et al., 2018), suggesting that DHA may be 85 critical for supporting visual signaling. Recently, Silver and colleagues showed that Mfsd2a is 86 expressed in retinal pigment epithelium (RPE) and retinal vasculature and that the Mfsd2a- 87 mediated lipid transport in RPE is particularly important for maintaining the high DHA 4 88 concentration in the retina (Wong et al., 2016). They reported that whole eyes of Mfsd2a-/- mice 89 contain ~40% less DHA than WT controls and that this decrease is compensated by an increase 90 in the content of arachidonic acid (AA). They also reported that Mfsd2a-/- photoreceptors appear 91 to have a morphological defect in their outer segment disc structure. Yet, their analysis of visual 92 function by electroretinography yielded nearly normal light responses. 93 Here, we analyzed the retinal phenotype of an alternative Mfsd2a-/- mouse strain, which 94 corroborated and expanded several key observations from the previous report (Wong et al., 95 2016), disagreed with two and revealed a number of novel findings (see Discussion for a detailed 96 comparison between the two studies). We have found that Mfsd2a-/- retinas undergo a global 97 remodeling of their fatty acid composition, including a 45% reduction in the fraction of DHA 98 lipids and a compensatory 66% increase in the fraction of AA. We also observed a 56% increase 99 in the fraction of phospholipids containing monounsaturated fatty acid moieties and a 57% loss 100 in phospholipids containing very long chain fatty acid moieties. Similar changes were observed 101 in an independently analyzed lipidome of isolated photoreceptor outer segment membranes. 102 Mfsd2a-/- photoreceptors underwent relatively slow progressive degeneration, although surviving 103 photoreceptors retained an entirely normal ultrastructure. Remarkably, single cell recording from 104 Mfsd2a-/- rods did not reveal any major phototransduction phenotype. This indicates that 105 impaired LPC supply to the retina and the corresponding ~2-fold reduction in the content of 106 retinal DHA are detrimental for long-term viability of photoreceptor cells, but do not impact the 107 ability of surviving cells to produce normal responses to light. 108 Materials and Methods 109 Animals. Frozen embryos of Mfsd2a heterozygote mice were purchased from the KOMP 110 repository (032467-UCD) and recovered by the Duke Transgenics Core. One of the recovered 5 111 heterozygous female mice was used as a founder. This is the same line as used in (Ben-Zvi et al., 112 2014; Chow and Gu, 2017), except that we back-crossed the line used in this study to the 113 C57BL/6J background (Jackson Labs, stock # 000664) for eight generations. The line was 114 negative for rd1 and rd8 mutations. Mice were maintained on the Teklad global 18% protein 115 rodent diet 2918 (Envigo, UK). At 1 month of age Mfsd2a-/- mice were on average ~25% smaller 116 than their WT littermates (14.8 ± 1.1 g vs.
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