Cell-Type-Specific Complement Profiling in the ABCA4 -/- Mouse Model of Stargardt Disease
Stargardt macular degeneration is an inherited retinal disease caused by mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene. Here, we characterized the complement expression profile in ABCA4 retinae and aligned these findings with morphological markers of retinal degeneration. W...
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creator | Jabri, Yassin Biber, Josef Diaz-Lezama, Nundehui Grosche, Antje Pauly, Diana |
description | Stargardt macular degeneration is an inherited retinal disease caused by mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene. Here, we characterized the complement expression profile in ABCA4
retinae and aligned these findings with morphological markers of retinal degeneration. We found an enhanced retinal pigment epithelium (RPE) autofluorescence, cell loss in the inner retina of ABCA4
mice and demonstrated age-related differences in complement expression in various retinal cell types irrespective of the genotype. However, 24-week-old ABCA4
mice expressed more
in the RPE and fewer
transcripts in the microglia compared to controls. At the protein level, the decrease of complement inhibitors (complement factor I, CFI) in retinae, as well as an increased C3b/C3 ratio in the RPE/choroid and retinae of ABCA4
, mice was confirmed. We showed a corresponding increase of the C3d/C3 ratio in the serum of ABCA4
mice, while no changes were observed for CFI. Our findings suggest an overactive complement cascade in the ABCA4
retinae that possibly contributes to pathological alterations, including microglial activation and neurodegeneration. Overall, this underpins the importance of well-balanced complement homeostasis to maintain retinal integrity. |
doi_str_mv | 10.3390/ijms21228468 |
format | Article |
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retinae and aligned these findings with morphological markers of retinal degeneration. We found an enhanced retinal pigment epithelium (RPE) autofluorescence, cell loss in the inner retina of ABCA4
mice and demonstrated age-related differences in complement expression in various retinal cell types irrespective of the genotype. However, 24-week-old ABCA4
mice expressed more
in the RPE and fewer
transcripts in the microglia compared to controls. At the protein level, the decrease of complement inhibitors (complement factor I, CFI) in retinae, as well as an increased C3b/C3 ratio in the RPE/choroid and retinae of ABCA4
, mice was confirmed. We showed a corresponding increase of the C3d/C3 ratio in the serum of ABCA4
mice, while no changes were observed for CFI. Our findings suggest an overactive complement cascade in the ABCA4
retinae that possibly contributes to pathological alterations, including microglial activation and neurodegeneration. Overall, this underpins the importance of well-balanced complement homeostasis to maintain retinal integrity.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms21228468</identifier><identifier>PMID: 33187113</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Age ; Aging ; Albinism ; Animals ; ATP-Binding Cassette Transporters - metabolism ; Choroid - metabolism ; Complement ; Complement activation ; Complement Activation - physiology ; Complement component C3 ; Complement component C3b ; Complement factor I ; Complement inhibitors ; Complement System Proteins - metabolism ; Diabetic retinopathy ; Disease ; Disease Models, Animal ; Epithelium ; Female ; Gene expression ; Genotype & phenotype ; Genotypes ; Homeostasis ; Macular degeneration ; Macular Degeneration - metabolism ; Male ; Mice ; Mice, Inbred BALB C ; Microglia ; Microglia - metabolism ; Mutation ; Neurodegeneration ; Oxidative stress ; Photoreceptors ; Ratios ; Retina ; Retina - metabolism ; Retinal cells ; Retinal degeneration ; Retinal Degeneration - metabolism ; Retinal pigment epithelium ; Retinal Pigment Epithelium - metabolism ; Stargardt Disease - metabolism</subject><ispartof>International journal of molecular sciences, 2020-11, Vol.21 (22), p.8468</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-8c85b3617922df2e90468a44417d7d9bc45a74f0f16b2454d6cd33a3684900d3</citedby><cites>FETCH-LOGICAL-c412t-8c85b3617922df2e90468a44417d7d9bc45a74f0f16b2454d6cd33a3684900d3</cites><orcidid>0000-0003-0338-7530 ; 0000-0002-1563-1601</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697683/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697683/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33187113$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jabri, Yassin</creatorcontrib><creatorcontrib>Biber, Josef</creatorcontrib><creatorcontrib>Diaz-Lezama, Nundehui</creatorcontrib><creatorcontrib>Grosche, Antje</creatorcontrib><creatorcontrib>Pauly, Diana</creatorcontrib><title>Cell-Type-Specific Complement Profiling in the ABCA4 -/- Mouse Model of Stargardt Disease</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Stargardt macular degeneration is an inherited retinal disease caused by mutations in the ATP-binding cassette subfamily A member 4 (ABCA4) gene. Here, we characterized the complement expression profile in ABCA4
retinae and aligned these findings with morphological markers of retinal degeneration. We found an enhanced retinal pigment epithelium (RPE) autofluorescence, cell loss in the inner retina of ABCA4
mice and demonstrated age-related differences in complement expression in various retinal cell types irrespective of the genotype. However, 24-week-old ABCA4
mice expressed more
in the RPE and fewer
transcripts in the microglia compared to controls. At the protein level, the decrease of complement inhibitors (complement factor I, CFI) in retinae, as well as an increased C3b/C3 ratio in the RPE/choroid and retinae of ABCA4
, mice was confirmed. We showed a corresponding increase of the C3d/C3 ratio in the serum of ABCA4
mice, while no changes were observed for CFI. Our findings suggest an overactive complement cascade in the ABCA4
retinae that possibly contributes to pathological alterations, including microglial activation and neurodegeneration. Overall, this underpins the importance of well-balanced complement homeostasis to maintain retinal integrity.</description><subject>Age</subject><subject>Aging</subject><subject>Albinism</subject><subject>Animals</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>Choroid - metabolism</subject><subject>Complement</subject><subject>Complement activation</subject><subject>Complement Activation - physiology</subject><subject>Complement component C3</subject><subject>Complement component C3b</subject><subject>Complement factor I</subject><subject>Complement inhibitors</subject><subject>Complement System Proteins - metabolism</subject><subject>Diabetic retinopathy</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Epithelium</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genotype & phenotype</subject><subject>Genotypes</subject><subject>Homeostasis</subject><subject>Macular degeneration</subject><subject>Macular Degeneration - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Microglia</subject><subject>Microglia - metabolism</subject><subject>Mutation</subject><subject>Neurodegeneration</subject><subject>Oxidative stress</subject><subject>Photoreceptors</subject><subject>Ratios</subject><subject>Retina</subject><subject>Retina - metabolism</subject><subject>Retinal cells</subject><subject>Retinal degeneration</subject><subject>Retinal Degeneration - metabolism</subject><subject>Retinal pigment epithelium</subject><subject>Retinal Pigment Epithelium - metabolism</subject><subject>Stargardt Disease - metabolism</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1rGzEQxUVpaBw3t5yDoJccsom-VtJeCs62SQouDcSXnIQsaW2Z3dVGWhf830etk-D2MjMwPx7z5gFwhtEVpRW69psuEUyIZFx-ABPMCCkQ4uLjwXwMTlLaIEQoKatP4JhSLAXGdAKeate2xWI3uOJxcMY33sA6dEPrOteP8CGGxre-X0Hfw3Ht4OymnjFYXBfwZ9gml6t1LQwNfBx1XOloR_jNJ6eT-wyOGt0md_rap2Bx-31R3xfzX3c_6tm8MAyTsZBGlkvKsagIsQ1xFco-NGMMCytstTSs1II1qMF8SVjJLDeWUk25ZBVClk7B173ssF12zpp8ddStGqLvdNypoL36d9P7tVqF30rwSnBJs8DFq0AMz1uXRtX5ZPJXdO-yRUUYR4JjTmVGv_yHbsI29tndX0pKLKsyU5d7ysSQUnTN-zEYqT-RqcPIMn5-aOAdfsuIvgB0uI_Z</recordid><startdate>20201111</startdate><enddate>20201111</enddate><creator>Jabri, Yassin</creator><creator>Biber, Josef</creator><creator>Diaz-Lezama, Nundehui</creator><creator>Grosche, Antje</creator><creator>Pauly, Diana</creator><general>MDPI AG</general><general>MDPI</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0338-7530</orcidid><orcidid>https://orcid.org/0000-0002-1563-1601</orcidid></search><sort><creationdate>20201111</creationdate><title>Cell-Type-Specific Complement Profiling in the ABCA4 -/- Mouse Model of Stargardt Disease</title><author>Jabri, Yassin ; 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Here, we characterized the complement expression profile in ABCA4
retinae and aligned these findings with morphological markers of retinal degeneration. We found an enhanced retinal pigment epithelium (RPE) autofluorescence, cell loss in the inner retina of ABCA4
mice and demonstrated age-related differences in complement expression in various retinal cell types irrespective of the genotype. However, 24-week-old ABCA4
mice expressed more
in the RPE and fewer
transcripts in the microglia compared to controls. At the protein level, the decrease of complement inhibitors (complement factor I, CFI) in retinae, as well as an increased C3b/C3 ratio in the RPE/choroid and retinae of ABCA4
, mice was confirmed. We showed a corresponding increase of the C3d/C3 ratio in the serum of ABCA4
mice, while no changes were observed for CFI. Our findings suggest an overactive complement cascade in the ABCA4
retinae that possibly contributes to pathological alterations, including microglial activation and neurodegeneration. Overall, this underpins the importance of well-balanced complement homeostasis to maintain retinal integrity.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33187113</pmid><doi>10.3390/ijms21228468</doi><orcidid>https://orcid.org/0000-0003-0338-7530</orcidid><orcidid>https://orcid.org/0000-0002-1563-1601</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Age Aging Albinism Animals ATP-Binding Cassette Transporters - metabolism Choroid - metabolism Complement Complement activation Complement Activation - physiology Complement component C3 Complement component C3b Complement factor I Complement inhibitors Complement System Proteins - metabolism Diabetic retinopathy Disease Disease Models, Animal Epithelium Female Gene expression Genotype & phenotype Genotypes Homeostasis Macular degeneration Macular Degeneration - metabolism Male Mice Mice, Inbred BALB C Microglia Microglia - metabolism Mutation Neurodegeneration Oxidative stress Photoreceptors Ratios Retina Retina - metabolism Retinal cells Retinal degeneration Retinal Degeneration - metabolism Retinal pigment epithelium Retinal Pigment Epithelium - metabolism Stargardt Disease - metabolism |
title | Cell-Type-Specific Complement Profiling in the ABCA4 -/- Mouse Model of Stargardt Disease |
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