Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph
| Autor(a) principal: | |
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| Data de Publicação: | 2019 |
| Outros Autores: | , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/54176 |
Resumo: | © The Author(s). 2019 Open Access © This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
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Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorphDementiaGenetic variantsImmune responseNeuroinflammationPhospholipase C© The Author(s). 2019 Open Access © This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background: Recent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset Alzheimer's disease (LOAD). Amongst these, a polymorphism in phospholipase C-gamma 2 (PLCG2) P522R has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function. Methods: We assessed PLCG2 distribution in human and mouse brain tissue via immunohistochemistry and in situ hybridization. We transfected heterologous cell systems (COS7 and HEK293T cells) to determine the effect of the P522R AD-associated variant on enzymatic function using various orthogonal assays, including a radioactive assay, IP-One ELISA, and calcium assays. Results: PLCG2 expression is restricted primarily to microglia and granule cells of the dentate gyrus. Plcg2 mRNA is maintained in plaque-associated microglia in the cerebral tissue of an AD mouse model. Functional analysis of the p.P522R variant demonstrated a small hypermorphic effect of the mutation on enzyme function. Conclusions: The PLCG2 P522R variant is protective against AD. We show that PLCG2 is expressed in brain microglia, and the p.P522R polymorphism weakly increases enzyme function. These data suggest that activation of PLCγ2 and not inhibition could be therapeutically beneficial in AD. PLCγ2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLCγ2 may be one potential therapeutic approach.The Mayo Clinic Alzheimer’s Disease Genetic Studies, led by Dr. Nilufer Taner and Dr. Steven G. Younkin, Mayo Clinic, Jacksonville, FL using samples from the Mayo Clinic Study of Aging, the Mayo Clinic Alzheimers Disease Research Center, and the Mayo Clinic Brain Bank. Data collection was supported through funding by NIA grants P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949, NINDS grant R01 NS080820, CurePSP Foundation, and support from Mayo Foundation. Study data includes samples collected through the Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinsons Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimers Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimers Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium) and the Michael J. Fox Foundation for Parkinsons Research. The UCL Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies and the Medical Research Council.Springer NatureRepositório da Universidade de LisboaMagno, LorenzaLessard, Christian B.Martins, MartaLang, VerenaCruz, PedroAsi, YasmineKatan, MatildaBilsland, JamieLashley, TammarynChakrabarty, ParamitaGolde, Todd E.Whiting, Paul J.2022-08-24T11:17:00Z20192019-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/54176engAlzheimers Res Ther. 2019 Feb 2;11(1):1610.1186/s13195-019-0469-01758-9193info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:59:43Zoai:repositorio.ul.pt:10451/54176Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:04:38.614442Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
| dc.title.none.fl_str_mv |
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph |
| title |
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph |
| spellingShingle |
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph Magno, Lorenza Dementia Genetic variants Immune response Neuroinflammation Phospholipase C |
| title_short |
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph |
| title_full |
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph |
| title_fullStr |
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph |
| title_full_unstemmed |
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph |
| title_sort |
Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph |
| author |
Magno, Lorenza |
| author_facet |
Magno, Lorenza Lessard, Christian B. Martins, Marta Lang, Verena Cruz, Pedro Asi, Yasmine Katan, Matilda Bilsland, Jamie Lashley, Tammaryn Chakrabarty, Paramita Golde, Todd E. Whiting, Paul J. |
| author_role |
author |
| author2 |
Lessard, Christian B. Martins, Marta Lang, Verena Cruz, Pedro Asi, Yasmine Katan, Matilda Bilsland, Jamie Lashley, Tammaryn Chakrabarty, Paramita Golde, Todd E. Whiting, Paul J. |
| author2_role |
author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
| dc.contributor.author.fl_str_mv |
Magno, Lorenza Lessard, Christian B. Martins, Marta Lang, Verena Cruz, Pedro Asi, Yasmine Katan, Matilda Bilsland, Jamie Lashley, Tammaryn Chakrabarty, Paramita Golde, Todd E. Whiting, Paul J. |
| dc.subject.por.fl_str_mv |
Dementia Genetic variants Immune response Neuroinflammation Phospholipase C |
| topic |
Dementia Genetic variants Immune response Neuroinflammation Phospholipase C |
| description |
© The Author(s). 2019 Open Access © This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
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2019 |
| dc.date.none.fl_str_mv |
2019 2019-01-01T00:00:00Z 2022-08-24T11:17:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
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http://hdl.handle.net/10451/54176 |
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http://hdl.handle.net/10451/54176 |
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eng |
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eng |
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Alzheimers Res Ther. 2019 Feb 2;11(1):16 10.1186/s13195-019-0469-0 1758-9193 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Springer Nature |
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Springer Nature |
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