Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins
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/10400.1/13403 |
Resumo: | Background Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. Results We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. Conclusions Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations. |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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7160 |
spelling |
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteinsBackground Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. Results We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. Conclusions Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations.This project has been financed through a) The ISCIII (Miguel Servet-I, 2015), co-financed by the European Regional Development Fund (ERDF), No CP15/00071. b) The European Union’s Horizon 2020 research and innovation program, under grant agreement No 634479. c) Regional Ministry of Economy, Innovation and Science of the Junta de Andalucía, No P09-CTS-04967.BMCSapientiaValdés-Sánchez, LourdesCalado, Sofiade la Cerda, BertaAramburu, AnaGarcía-Delgado, Ana BMassalini, SimoneMontero-Sánchez, AdoraciónBhatia, VaibhavRodríguez-Bocanegra, EduardoDiez-Lloret, AndreaRodríguez-Martínez, DanielChakarova, ChristinaBhattacharya, Shom SDíaz-Corrales, Francisco J2020-01-06T15:10:35Z2019-12-312020-01-01T04:35:13Z2019-12-31T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/13403engMolecular Medicine. 2019 Dec 31;26(1):1s10020-019-0124-zinfo: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:RCAAP2023-07-24T10:25:31Zoai:sapientia.ualg.pt:10400.1/13403Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:04:35.987004Repositório 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 |
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
title |
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
spellingShingle |
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins Valdés-Sánchez, Lourdes |
title_short |
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
title_full |
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
title_fullStr |
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
title_full_unstemmed |
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
title_sort |
Retinal pigment epithelium degeneration caused by aggregation of PRPF31 and the role of HSP70 family of proteins |
author |
Valdés-Sánchez, Lourdes |
author_facet |
Valdés-Sánchez, Lourdes Calado, Sofia de la Cerda, Berta Aramburu, Ana García-Delgado, Ana B Massalini, Simone Montero-Sánchez, Adoración Bhatia, Vaibhav Rodríguez-Bocanegra, Eduardo Diez-Lloret, Andrea Rodríguez-Martínez, Daniel Chakarova, Christina Bhattacharya, Shom S Díaz-Corrales, Francisco J |
author_role |
author |
author2 |
Calado, Sofia de la Cerda, Berta Aramburu, Ana García-Delgado, Ana B Massalini, Simone Montero-Sánchez, Adoración Bhatia, Vaibhav Rodríguez-Bocanegra, Eduardo Diez-Lloret, Andrea Rodríguez-Martínez, Daniel Chakarova, Christina Bhattacharya, Shom S Díaz-Corrales, Francisco J |
author2_role |
author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Sapientia |
dc.contributor.author.fl_str_mv |
Valdés-Sánchez, Lourdes Calado, Sofia de la Cerda, Berta Aramburu, Ana García-Delgado, Ana B Massalini, Simone Montero-Sánchez, Adoración Bhatia, Vaibhav Rodríguez-Bocanegra, Eduardo Diez-Lloret, Andrea Rodríguez-Martínez, Daniel Chakarova, Christina Bhattacharya, Shom S Díaz-Corrales, Francisco J |
description |
Background Mutations in pre-mRNA splicing factor PRPF31 can lead to retinitis pigmentosa (RP). Although the exact disease mechanism remains unknown, it has been hypothesized that haploinsufficiency might be involved in the pathophysiology of the disease. Methods In this study, we have analyzed a mouse model containing the p.A216P mutation in Prpf31 gene. Results We found that mutant Prpf31 protein produces cytoplasmic aggregates in the retinal pigment epithelium and decreasing the protein levels of this splicing factor in the nucleus. Additionally, normal protein was recruited in insoluble aggregates when the mutant protein was overexpressed in vitro. In response to protein aggregation, Hspa4l is overexpressed. This member of the HSP70 family of chaperones might contribute to the correct folding and solubilization of the mutant protein, allowing its translocation to the nucleus. Conclusions Our data suggests that a mechanism haploinsufficiency and dominant-negative is involved in retinal degeneration due to mutations in PRPF31. HSP70 over-expression might be a new therapeutic target for the treatment of retinal degeneration due to PRPF31 mutations. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-12-31 2019-12-31T00:00:00Z 2020-01-06T15:10:35Z 2020-01-01T04:35:13Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10400.1/13403 |
url |
http://hdl.handle.net/10400.1/13403 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Molecular Medicine. 2019 Dec 31;26(1):1 s10020-019-0124-z |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
BMC |
publisher.none.fl_str_mv |
BMC |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133283277078528 |