Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis
Autor(a) principal: | |
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Data de Publicação: | 2017 |
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/10400.1/13336 |
Resumo: | Proteolytic cleavage has been implicated in the pathogenesis of diverse neurodegenerative diseases involving abnormal protein accumulation. Polyglutamine diseases are a group of nine hereditary disorders caused by an abnormal expansion of repeated glutamine tracts contained in otherwise unrelated proteins. When expanded, these proteins display toxic properties and are prone to aggregate, but the mechanisms responsible for the selective neurodegeneration observed in polyglutamine disease patients are still poorly understood. It has been suggested that the neuronal toxicity of polyglutamine-expanded proteins is associated with the production of deleterious protein fragments. This review aims at discussing the involvement of proteolytic cleavage in the six types of spinocerebellar ataxia caused by polyglutamine expansion of proteins. The analysis takes into detailed consideration evidence concerning fragment detection and the mechanisms of fragment toxicity. Current evidence suggests that the proteins involved in spinocerebellar ataxia types 3, 6 and 7 give rise to stable proteolytic fragments. Fragments carrying polyglutamine expansions display increased tendency to aggregate and toxicity, comparing with their non-expanded counterparts or with the correspondent full-length expanded proteins. Data concerning spinocerebellar ataxia types 1, 2 and 17 is still scarce, but available results afford further investigation. Available literature suggests that proteolytic cleavage of expanded polyglutamine-containing proteins enhances toxicity in disease-associated contexts and may constitute an important step in the pathogenic cascade of polyglutamine diseases. Countering protein fragmentation thus presents itself as a promising therapeutic aim. |
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Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesisMachado-joseph-diseaseSpinocerebellar ataxia type-3Dominant cerebellar-ataxiaTata-binding proteinNeuronal intranuclear inclusionsExpanded androgen receptorSoluble amyloid oligomersBulbar muscular-atrophyDentatorubral-pallidoluysian atrophyDeubiquitinating Enzyme Ataxin-3Proteolytic cleavage has been implicated in the pathogenesis of diverse neurodegenerative diseases involving abnormal protein accumulation. Polyglutamine diseases are a group of nine hereditary disorders caused by an abnormal expansion of repeated glutamine tracts contained in otherwise unrelated proteins. When expanded, these proteins display toxic properties and are prone to aggregate, but the mechanisms responsible for the selective neurodegeneration observed in polyglutamine disease patients are still poorly understood. It has been suggested that the neuronal toxicity of polyglutamine-expanded proteins is associated with the production of deleterious protein fragments. This review aims at discussing the involvement of proteolytic cleavage in the six types of spinocerebellar ataxia caused by polyglutamine expansion of proteins. The analysis takes into detailed consideration evidence concerning fragment detection and the mechanisms of fragment toxicity. Current evidence suggests that the proteins involved in spinocerebellar ataxia types 3, 6 and 7 give rise to stable proteolytic fragments. Fragments carrying polyglutamine expansions display increased tendency to aggregate and toxicity, comparing with their non-expanded counterparts or with the correspondent full-length expanded proteins. Data concerning spinocerebellar ataxia types 1, 2 and 17 is still scarce, but available results afford further investigation. Available literature suggests that proteolytic cleavage of expanded polyglutamine-containing proteins enhances toxicity in disease-associated contexts and may constitute an important step in the pathogenic cascade of polyglutamine diseases. Countering protein fragmentation thus presents itself as a promising therapeutic aim.FEDER through the Competitive Factors Operational Program-COMPETE [CENTRO-07-ST24-FEDER-002002]FEDER through National Funds (PIDDAC)Portuguese Foundation for Science and Technology (FCT) [UID/NEU/ 04539/2013, E-Rare4/0003/2012]French Muscular Dystrophy Association (AFM)National Ataxia Foundation (NAF)Richard Chin and Lily Lock Machado-Joseph disease Research FundPortuguese Science Foundation (FCT)[01/BIDJPND_Synspread/2016]Bentham Science Publ LtdSapientiaMatos, Carlos A.de Almeida, Lus PereiraNóbrega, Clévio2019-11-20T15:08:03Z20172017-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.1/13336eng1381-612810.2174/1381612822666161227info: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:RCAAP2023-07-24T10:25:26Zoai:sapientia.ualg.pt:10400.1/13336Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:04:29.796092Repositório 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 |
Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis |
title |
Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis |
spellingShingle |
Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis Matos, Carlos A. Machado-joseph-disease Spinocerebellar ataxia type-3 Dominant cerebellar-ataxia Tata-binding protein Neuronal intranuclear inclusions Expanded androgen receptor Soluble amyloid oligomers Bulbar muscular-atrophy Dentatorubral-pallidoluysian atrophy Deubiquitinating Enzyme Ataxin-3 |
title_short |
Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis |
title_full |
Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis |
title_fullStr |
Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis |
title_full_unstemmed |
Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis |
title_sort |
Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis |
author |
Matos, Carlos A. |
author_facet |
Matos, Carlos A. de Almeida, Lus Pereira Nóbrega, Clévio |
author_role |
author |
author2 |
de Almeida, Lus Pereira Nóbrega, Clévio |
author2_role |
author author |
dc.contributor.none.fl_str_mv |
Sapientia |
dc.contributor.author.fl_str_mv |
Matos, Carlos A. de Almeida, Lus Pereira Nóbrega, Clévio |
dc.subject.por.fl_str_mv |
Machado-joseph-disease Spinocerebellar ataxia type-3 Dominant cerebellar-ataxia Tata-binding protein Neuronal intranuclear inclusions Expanded androgen receptor Soluble amyloid oligomers Bulbar muscular-atrophy Dentatorubral-pallidoluysian atrophy Deubiquitinating Enzyme Ataxin-3 |
topic |
Machado-joseph-disease Spinocerebellar ataxia type-3 Dominant cerebellar-ataxia Tata-binding protein Neuronal intranuclear inclusions Expanded androgen receptor Soluble amyloid oligomers Bulbar muscular-atrophy Dentatorubral-pallidoluysian atrophy Deubiquitinating Enzyme Ataxin-3 |
description |
Proteolytic cleavage has been implicated in the pathogenesis of diverse neurodegenerative diseases involving abnormal protein accumulation. Polyglutamine diseases are a group of nine hereditary disorders caused by an abnormal expansion of repeated glutamine tracts contained in otherwise unrelated proteins. When expanded, these proteins display toxic properties and are prone to aggregate, but the mechanisms responsible for the selective neurodegeneration observed in polyglutamine disease patients are still poorly understood. It has been suggested that the neuronal toxicity of polyglutamine-expanded proteins is associated with the production of deleterious protein fragments. This review aims at discussing the involvement of proteolytic cleavage in the six types of spinocerebellar ataxia caused by polyglutamine expansion of proteins. The analysis takes into detailed consideration evidence concerning fragment detection and the mechanisms of fragment toxicity. Current evidence suggests that the proteins involved in spinocerebellar ataxia types 3, 6 and 7 give rise to stable proteolytic fragments. Fragments carrying polyglutamine expansions display increased tendency to aggregate and toxicity, comparing with their non-expanded counterparts or with the correspondent full-length expanded proteins. Data concerning spinocerebellar ataxia types 1, 2 and 17 is still scarce, but available results afford further investigation. Available literature suggests that proteolytic cleavage of expanded polyglutamine-containing proteins enhances toxicity in disease-associated contexts and may constitute an important step in the pathogenic cascade of polyglutamine diseases. Countering protein fragmentation thus presents itself as a promising therapeutic aim. |
publishDate |
2017 |
dc.date.none.fl_str_mv |
2017 2017-01-01T00:00:00Z 2019-11-20T15:08:03Z |
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/10400.1/13336 |
url |
http://hdl.handle.net/10400.1/13336 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1381-6128 10.2174/1381612822666161227 |
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 |
Bentham Science Publ Ltd |
publisher.none.fl_str_mv |
Bentham Science Publ Ltd |
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 |
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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) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133282189705216 |