Glycation potentiates neurodegeneration in models of Huntington's disease
Autor(a) principal: | |
---|---|
Data de Publicação: | 2016 |
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/10362/22380 |
Resumo: | Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying aminogroups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models. We found that glycation impairs HTT clearance thereby promoting its intracellular accumulation and aggregation. Interestingly, under these conditions autophagy increased and the levels of mutant HTT released to the culture medium decreased. Furthermore, increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity, and suggests it may constitute a novel target for therapeutic intervention in HD. |
id |
RCAP_d0d2c18b29c11d6434f225fdb9dec0ed |
---|---|
oai_identifier_str |
oai:run.unl.pt:10362/22380 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
spelling |
Glycation potentiates neurodegeneration in models of Huntington's diseaseSDG 3 - Good Health and Well-beingProtein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying aminogroups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models. We found that glycation impairs HTT clearance thereby promoting its intracellular accumulation and aggregation. Interestingly, under these conditions autophagy increased and the levels of mutant HTT released to the culture medium decreased. Furthermore, increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity, and suggests it may constitute a novel target for therapeutic intervention in HD.NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)Centro de Estudos de Doenças Crónicas (CEDOC)Instituto de Tecnologia Química e Biológica António Xavier (ITQB)RUNMiranda, Hugo VicenteGomes, Marcos AntonioBranco-Santos, JoanaBreda, CarloLazaro, Diana FLopes, Lusa VaqueiroHerrera, FedericoGiorgini, FlavianoOuteiro, Tiago F2017-08-01T22:03:22Z2016-11-182016-11-18T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/22380eng2045-2322PURE: 2354717https://doi.org/10.1038/srep36798info: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:RCAAP2024-03-11T04:09:50Zoai:run.unl.pt:10362/22380Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:27:15.655020Repositório 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 |
Glycation potentiates neurodegeneration in models of Huntington's disease |
title |
Glycation potentiates neurodegeneration in models of Huntington's disease |
spellingShingle |
Glycation potentiates neurodegeneration in models of Huntington's disease Miranda, Hugo Vicente SDG 3 - Good Health and Well-being |
title_short |
Glycation potentiates neurodegeneration in models of Huntington's disease |
title_full |
Glycation potentiates neurodegeneration in models of Huntington's disease |
title_fullStr |
Glycation potentiates neurodegeneration in models of Huntington's disease |
title_full_unstemmed |
Glycation potentiates neurodegeneration in models of Huntington's disease |
title_sort |
Glycation potentiates neurodegeneration in models of Huntington's disease |
author |
Miranda, Hugo Vicente |
author_facet |
Miranda, Hugo Vicente Gomes, Marcos Antonio Branco-Santos, Joana Breda, Carlo Lazaro, Diana F Lopes, Lusa Vaqueiro Herrera, Federico Giorgini, Flaviano Outeiro, Tiago F |
author_role |
author |
author2 |
Gomes, Marcos Antonio Branco-Santos, Joana Breda, Carlo Lazaro, Diana F Lopes, Lusa Vaqueiro Herrera, Federico Giorgini, Flaviano Outeiro, Tiago F |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) Centro de Estudos de Doenças Crónicas (CEDOC) Instituto de Tecnologia Química e Biológica António Xavier (ITQB) RUN |
dc.contributor.author.fl_str_mv |
Miranda, Hugo Vicente Gomes, Marcos Antonio Branco-Santos, Joana Breda, Carlo Lazaro, Diana F Lopes, Lusa Vaqueiro Herrera, Federico Giorgini, Flaviano Outeiro, Tiago F |
dc.subject.por.fl_str_mv |
SDG 3 - Good Health and Well-being |
topic |
SDG 3 - Good Health and Well-being |
description |
Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying aminogroups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models. We found that glycation impairs HTT clearance thereby promoting its intracellular accumulation and aggregation. Interestingly, under these conditions autophagy increased and the levels of mutant HTT released to the culture medium decreased. Furthermore, increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity, and suggests it may constitute a novel target for therapeutic intervention in HD. |
publishDate |
2016 |
dc.date.none.fl_str_mv |
2016-11-18 2016-11-18T00:00:00Z 2017-08-01T22:03:22Z |
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/10362/22380 |
url |
http://hdl.handle.net/10362/22380 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
2045-2322 PURE: 2354717 https://doi.org/10.1038/srep36798 |
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.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 |
instname_str |
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) |
collection |
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 |
repository.mail.fl_str_mv |
|
_version_ |
1799137901588512768 |