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Proteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis

2017Journal article Open access
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dc.contributor.authorMatos, Carlos A.
dc.contributor.authorde Almeida, Lus Pereira
dc.contributor.authorNóbrega, Clévio
dc.date.accessioned2019-11-20T15:08:03Z
dc.date.available2019-11-20T15:08:03Z
dc.date.issued2017
dc.description.abstractProteolytic 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.
dc.description.sponsorshipFEDER through the Competitive Factors Operational Program-COMPETE [CENTRO-07-ST24-FEDER-002002]
dc.description.sponsorshipFEDER through National Funds (PIDDAC)
dc.description.sponsorshipPortuguese Foundation for Science and Technology (FCT) [UID/NEU/ 04539/2013, E-Rare4/0003/2012]
dc.description.sponsorshipFrench Muscular Dystrophy Association (AFM)
dc.description.sponsorshipNational Ataxia Foundation (NAF)
dc.description.sponsorshipRichard Chin and Lily Lock Machado-Joseph disease Research Fund
dc.description.sponsorshipPortuguese Science Foundation (FCT)
dc.description.sponsorship[01/BIDJPND_Synspread/2016]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.2174/1381612822666161227
dc.identifier.issn1381-6128
dc.identifier.issn1873-4286
dc.identifier.urihttp://hdl.handle.net/10400.1/13336
dc.language.isoeng
dc.peerreviewedyes
dc.publisherBentham Science Publ Ltd
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectMachado-joseph-disease
dc.subjectSpinocerebellar ataxia type-3
dc.subjectDominant cerebellar-ataxia
dc.subjectTata-binding protein
dc.subjectNeuronal intranuclear inclusions
dc.subjectExpanded androgen receptor
dc.subjectSoluble amyloid oligomers
dc.subjectBulbar muscular-atrophy
dc.subjectDentatorubral-pallidoluysian atrophy
dc.subjectDeubiquitinating Enzyme Ataxin-3
dc.titleProteolytic cleavage of polyglutamine disease-causing proteins: Revisiting the toxic fragment hypothesis
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDTI/E-Rare4%2F0003%2F2012/PT
oaire.citation.endPage775
oaire.citation.issue5
oaire.citation.startPage753
oaire.citation.titleCurrent Pharmaceutical Design
oaire.citation.volume23
oaire.fundingStream3599-PPCDTI
person.familyNameNóbrega
person.givenNameClévio
person.identifier.ciencia-idC510-7F41-BAF8
person.identifier.orcid0000-0002-8312-5292
person.identifier.ridM-6047-2013
person.identifier.scopus-author-id24473454000
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublication725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
relation.isAuthorOfPublication.latestForDiscovery725ea6f8-1363-4cee-9cf2-5ac7303b3ba9
relation.isProjectOfPublication69b799e4-fdb7-4d42-bbc2-af05c180dde9
relation.isProjectOfPublication.latestForDiscovery69b799e4-fdb7-4d42-bbc2-af05c180dde9

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