The loss of microglia activities facilitates glaucoma progression in association with CYP1B1 gene mutation (p.Gly61Glu)
Glaucoma represents the second main cause of irreversible loss of eyesight worldwide. Progression of the disease is due to changes around the optic nerve, eye structure and optic nerve environment. Focusing on primary congenital glaucoma, which is not completely understood, we report an evaluation o...
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| description | Glaucoma represents the second main cause of irreversible loss of eyesight worldwide. Progression of the disease is due to changes around the optic nerve, eye structure and optic nerve environment. Focusing on primary congenital glaucoma, which is not completely understood, we report an evaluation of an untested mutation (c.182G>A, p.Gly61Glu) within the CYP1B1 gene in the context of microglia, astrocytes and mesenchymal stem cells. We investigated the behaviours of these cells, which are needed to maintain eye homeostasis, in response to the CYP1B1 mutation.
CRISPR technology was used to edit normal CYP1B1 genes within normal astrocytes, microglia and stem cells in vitro. Increased metabolic activities were found in microglia and astrocytes 24 hours after CYP1B1 manipulation. However, these activities dropped by 40% after 72 hrs. In addition, the nicotinamide adenine dinucleotide phosphate (NADP)/NADPH reducing equivalent process decreased by 50% on average after 72 hrs of manipulation. The cytokines measured in mutated microglia showed progressive activation leading to apoptosis, which was confirmed with annexin-V. The cytokines evaluated in mutant astrocytes were abnormal in comparison to those in the control.
The results suggest a progressive inflammation that was induced by mutations (p.Gly61Glu) on CYP1B1. Furthermore, the mutations enhanced the microglia's loss of activity. We are the first to show the direct impact of the mutation on microglia. This progressive inflammation might be responsible for primary congenital glaucoma complications, which could be avoided via an anti-inflammatory regimen. This finding also reveals that progressive inflammation affects recovery failure after surgeries to relieve glaucoma. Moreover, microglia are important for the survival of ganglion cells, along with the clearing of pathogens and inflammation. The reduction of their activities may jeopardise homeostasis within the optic nerve environment and complicate the protection of optic nerve components (such as retinal ganglion and glial cells). |
| doi_str_mv | 10.1371/journal.pone.0241902 |
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CRISPR technology was used to edit normal CYP1B1 genes within normal astrocytes, microglia and stem cells in vitro. Increased metabolic activities were found in microglia and astrocytes 24 hours after CYP1B1 manipulation. However, these activities dropped by 40% after 72 hrs. In addition, the nicotinamide adenine dinucleotide phosphate (NADP)/NADPH reducing equivalent process decreased by 50% on average after 72 hrs of manipulation. The cytokines measured in mutated microglia showed progressive activation leading to apoptosis, which was confirmed with annexin-V. The cytokines evaluated in mutant astrocytes were abnormal in comparison to those in the control.
The results suggest a progressive inflammation that was induced by mutations (p.Gly61Glu) on CYP1B1. Furthermore, the mutations enhanced the microglia's loss of activity. We are the first to show the direct impact of the mutation on microglia. This progressive inflammation might be responsible for primary congenital glaucoma complications, which could be avoided via an anti-inflammatory regimen. This finding also reveals that progressive inflammation affects recovery failure after surgeries to relieve glaucoma. Moreover, microglia are important for the survival of ganglion cells, along with the clearing of pathogens and inflammation. The reduction of their activities may jeopardise homeostasis within the optic nerve environment and complicate the protection of optic nerve components (such as retinal ganglion and glial cells).</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0241902</identifier><identifier>PMID: 33170892</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenine ; Amino Acid Substitution ; Animals ; Antibiotics ; Apoptosis ; Astrocytes ; Astrocytes - cytology ; Astrocytes - metabolism ; Biochemistry ; Biology and Life Sciences ; Brain research ; Care and treatment ; Cell Proliferation ; Cell survival ; Cells, Cultured ; Complications ; CRISPR ; CRISPR-Cas Systems ; CYP1B1 gene ; Cytochrome P-450 ; Cytochrome P-450 CYP1B1 - genetics ; Cytokines ; Cytokines - metabolism ; Development and progression ; Enzymes ; Evaluation ; Eye ; Ganglion cells ; Gene mutation ; Genetic aspects ; Glaucoma ; Glaucoma - congenital ; Glaucoma - genetics ; Glial cells ; Health aspects ; Homeostasis ; Humans ; Inflammation ; Kinases ; Male ; Medical research ; Medicine and Health Sciences ; Mesenchymal stem cells ; Mesenchymal Stem Cells - cytology ; Mesenchymal Stem Cells - metabolism ; Mesenchyme ; Microglia ; Microglia - cytology ; Microglia - metabolism ; Models, Animal ; Mutation ; NADP ; NADP - metabolism ; NADPH-diaphorase ; Nicotinamide ; Nicotinamide adenine dinucleotide ; Optic nerve ; Point Mutation ; Rats ; Reagents ; Stem cells ; Surgery</subject><ispartof>PloS one, 2020-11, Vol.15 (11), p.e0241902</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Alghamdi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Alghamdi et al 2020 Alghamdi et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-e5f95251232ded90e992a95728ffceb0944a39f78668be5c718730812b910613</citedby><cites>FETCH-LOGICAL-c692t-e5f95251232ded90e992a95728ffceb0944a39f78668be5c718730812b910613</cites><orcidid>0000-0002-5740-9187</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/PMC7654781/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654781/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33170892$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Alghamdi, Amani</creatorcontrib><creatorcontrib>Aldossary, Wadha</creatorcontrib><creatorcontrib>Albahkali, Sarah</creatorcontrib><creatorcontrib>Alotaibi, Batoul</creatorcontrib><creatorcontrib>Alrfaei, Bahauddeen M</creatorcontrib><title>The loss of microglia activities facilitates glaucoma progression in association with CYP1B1 gene mutation (p.Gly61Glu)</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Glaucoma represents the second main cause of irreversible loss of eyesight worldwide. Progression of the disease is due to changes around the optic nerve, eye structure and optic nerve environment. Focusing on primary congenital glaucoma, which is not completely understood, we report an evaluation of an untested mutation (c.182G>A, p.Gly61Glu) within the CYP1B1 gene in the context of microglia, astrocytes and mesenchymal stem cells. We investigated the behaviours of these cells, which are needed to maintain eye homeostasis, in response to the CYP1B1 mutation.
CRISPR technology was used to edit normal CYP1B1 genes within normal astrocytes, microglia and stem cells in vitro. Increased metabolic activities were found in microglia and astrocytes 24 hours after CYP1B1 manipulation. However, these activities dropped by 40% after 72 hrs. In addition, the nicotinamide adenine dinucleotide phosphate (NADP)/NADPH reducing equivalent process decreased by 50% on average after 72 hrs of manipulation. The cytokines measured in mutated microglia showed progressive activation leading to apoptosis, which was confirmed with annexin-V. The cytokines evaluated in mutant astrocytes were abnormal in comparison to those in the control.
The results suggest a progressive inflammation that was induced by mutations (p.Gly61Glu) on CYP1B1. Furthermore, the mutations enhanced the microglia's loss of activity. We are the first to show the direct impact of the mutation on microglia. This progressive inflammation might be responsible for primary congenital glaucoma complications, which could be avoided via an anti-inflammatory regimen. This finding also reveals that progressive inflammation affects recovery failure after surgeries to relieve glaucoma. Moreover, microglia are important for the survival of ganglion cells, along with the clearing of pathogens and inflammation. The reduction of their activities may jeopardise homeostasis within the optic nerve environment and complicate the protection of optic nerve components (such as retinal ganglion and glial cells).</description><subject>Adenine</subject><subject>Amino Acid Substitution</subject><subject>Animals</subject><subject>Antibiotics</subject><subject>Apoptosis</subject><subject>Astrocytes</subject><subject>Astrocytes - cytology</subject><subject>Astrocytes - metabolism</subject><subject>Biochemistry</subject><subject>Biology and Life Sciences</subject><subject>Brain research</subject><subject>Care and treatment</subject><subject>Cell Proliferation</subject><subject>Cell survival</subject><subject>Cells, Cultured</subject><subject>Complications</subject><subject>CRISPR</subject><subject>CRISPR-Cas Systems</subject><subject>CYP1B1 gene</subject><subject>Cytochrome P-450</subject><subject>Cytochrome P-450 CYP1B1 - genetics</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Development and progression</subject><subject>Enzymes</subject><subject>Evaluation</subject><subject>Eye</subject><subject>Ganglion cells</subject><subject>Gene mutation</subject><subject>Genetic aspects</subject><subject>Glaucoma</subject><subject>Glaucoma - congenital</subject><subject>Glaucoma - genetics</subject><subject>Glial cells</subject><subject>Health aspects</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Kinases</subject><subject>Male</subject><subject>Medical research</subject><subject>Medicine and Health Sciences</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stem Cells - cytology</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Mesenchyme</subject><subject>Microglia</subject><subject>Microglia - cytology</subject><subject>Microglia - metabolism</subject><subject>Models, Animal</subject><subject>Mutation</subject><subject>NADP</subject><subject>NADP - metabolism</subject><subject>NADPH-diaphorase</subject><subject>Nicotinamide</subject><subject>Nicotinamide adenine dinucleotide</subject><subject>Optic nerve</subject><subject>Point Mutation</subject><subject>Rats</subject><subject>Reagents</subject><subject>Stem cells</subject><subject>Surgery</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1rFDEUhgdRbK3-A9GAIPZi13xNZnIj1EXXhUJFF8GrkMkms1kyk-kk09p_b9adlh1QkFwkOXnOm5OTN8teIjhHpEDvd37oW-nmnW_1HGKKOMSPslPECZ4xDMnjo_VJ9iyEHYQ5KRl7mp0QggpYcnya3a63GjgfAvAGNFb1vnZWAqmivbHR6gCMVNbZKGNa104OyjcSdInrdQjWt8C2QIbglZVxv721cQsWP7-ijwjUutWgGeLh5F03X7o7hpZuOH-ePTHSBf1inM-y9edP68WX2eXVcrW4uJwpxnGc6dzwHOcIE7zRGw4151jyvMClMUpXkFMqCTdFelZZ6VwVqCwILBGuOIIMkbPs9UG2S28UY8uCwDTnuOCM0USsDsTGy53oetvI_k54acWfgO9rIftoldNCc2SwUgpTWlJZ8Uql4ijnZcUN1FAmrQ_jbUPV6I3Sbeylm4hOT1q7FbW_EQXLaVHuy30zCvT-etAh_qPkkaplqsq2xicx1digxAWjCFFcsjxR879QaWx0-udkGmNTfJJwPklITNS_Yi2HEMTq-7f_Z69-TNm3R-xWSxe3wbth74kwBekBTC4ModfmoXMIir3n77sh9p4Xo-dT2qvjrj8k3Zuc_AbPFfwD</recordid><startdate>20201110</startdate><enddate>20201110</enddate><creator>Alghamdi, Amani</creator><creator>Aldossary, Wadha</creator><creator>Albahkali, Sarah</creator><creator>Alotaibi, Batoul</creator><creator>Alrfaei, Bahauddeen M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-5740-9187</orcidid></search><sort><creationdate>20201110</creationdate><title>The loss of microglia activities facilitates glaucoma progression in association with CYP1B1 gene mutation (p.Gly61Glu)</title><author>Alghamdi, Amani ; Aldossary, Wadha ; Albahkali, Sarah ; Alotaibi, Batoul ; Alrfaei, Bahauddeen M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-e5f95251232ded90e992a95728ffceb0944a39f78668be5c718730812b910613</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenine</topic><topic>Amino Acid Substitution</topic><topic>Animals</topic><topic>Antibiotics</topic><topic>Apoptosis</topic><topic>Astrocytes</topic><topic>Astrocytes - 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Progression of the disease is due to changes around the optic nerve, eye structure and optic nerve environment. Focusing on primary congenital glaucoma, which is not completely understood, we report an evaluation of an untested mutation (c.182G>A, p.Gly61Glu) within the CYP1B1 gene in the context of microglia, astrocytes and mesenchymal stem cells. We investigated the behaviours of these cells, which are needed to maintain eye homeostasis, in response to the CYP1B1 mutation.
CRISPR technology was used to edit normal CYP1B1 genes within normal astrocytes, microglia and stem cells in vitro. Increased metabolic activities were found in microglia and astrocytes 24 hours after CYP1B1 manipulation. However, these activities dropped by 40% after 72 hrs. In addition, the nicotinamide adenine dinucleotide phosphate (NADP)/NADPH reducing equivalent process decreased by 50% on average after 72 hrs of manipulation. The cytokines measured in mutated microglia showed progressive activation leading to apoptosis, which was confirmed with annexin-V. The cytokines evaluated in mutant astrocytes were abnormal in comparison to those in the control.
The results suggest a progressive inflammation that was induced by mutations (p.Gly61Glu) on CYP1B1. Furthermore, the mutations enhanced the microglia's loss of activity. We are the first to show the direct impact of the mutation on microglia. This progressive inflammation might be responsible for primary congenital glaucoma complications, which could be avoided via an anti-inflammatory regimen. This finding also reveals that progressive inflammation affects recovery failure after surgeries to relieve glaucoma. Moreover, microglia are important for the survival of ganglion cells, along with the clearing of pathogens and inflammation. The reduction of their activities may jeopardise homeostasis within the optic nerve environment and complicate the protection of optic nerve components (such as retinal ganglion and glial cells).</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>33170892</pmid><doi>10.1371/journal.pone.0241902</doi><tpages>e0241902</tpages><orcidid>https://orcid.org/0000-0002-5740-9187</orcidid><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_2459279664 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adenine Amino Acid Substitution Animals Antibiotics Apoptosis Astrocytes Astrocytes - cytology Astrocytes - metabolism Biochemistry Biology and Life Sciences Brain research Care and treatment Cell Proliferation Cell survival Cells, Cultured Complications CRISPR CRISPR-Cas Systems CYP1B1 gene Cytochrome P-450 Cytochrome P-450 CYP1B1 - genetics Cytokines Cytokines - metabolism Development and progression Enzymes Evaluation Eye Ganglion cells Gene mutation Genetic aspects Glaucoma Glaucoma - congenital Glaucoma - genetics Glial cells Health aspects Homeostasis Humans Inflammation Kinases Male Medical research Medicine and Health Sciences Mesenchymal stem cells Mesenchymal Stem Cells - cytology Mesenchymal Stem Cells - metabolism Mesenchyme Microglia Microglia - cytology Microglia - metabolism Models, Animal Mutation NADP NADP - metabolism NADPH-diaphorase Nicotinamide Nicotinamide adenine dinucleotide Optic nerve Point Mutation Rats Reagents Stem cells Surgery |
| title | The loss of microglia activities facilitates glaucoma progression in association with CYP1B1 gene mutation (p.Gly61Glu) |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T02%3A09%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20loss%20of%20microglia%20activities%20facilitates%20glaucoma%20progression%20in%20association%20with%20CYP1B1%20gene%20mutation%20(p.Gly61Glu)&rft.jtitle=PloS%20one&rft.au=Alghamdi,%20Amani&rft.date=2020-11-10&rft.volume=15&rft.issue=11&rft.spage=e0241902&rft.pages=e0241902-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0241902&rft_dat=%3Cgale_plos_%3EA641142865%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2459279664&rft_id=info:pmid/33170892&rft_galeid=A641142865&rft_doaj_id=oai_doaj_org_article_e91f2ccc24484ab9bcf954998b9f0e0a&rfr_iscdi=true |