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The stress granule protein G3BP1 alleviates spinocerebellar ataxia-associated deficits

2022Journal article Open Access
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dc.contributor.authorKoppenol, Rebekah
dc.contributor.authorConceição, André
dc.contributor.authorAfonso, Inês T.
dc.contributor.authorAfonso-Reis, Ricardo
dc.contributor.authorCosta, Rafael G
dc.contributor.authorTomé, Sandra
dc.contributor.authorTeixeira, Diogo
dc.contributor.authorPinto-da-Silva, Joana
dc.contributor.authorCodêsso, José Miguel
dc.contributor.authorBrito, David V.C.
dc.contributor.authorMendonça, Liliana
dc.contributor.authorMarcelo, Adriana
dc.contributor.authorPereira de Almeida, Luís
dc.contributor.authorMatos, Carlos A
dc.contributor.authorNóbrega, Clévio
dc.date.accessioned2023-03-29T08:18:51Z
dc.date.available2023-03-29T08:18:51Z
dc.date.issued2022
dc.description.abstractKoppenol et al. show that overexpression of G3BP1 in cell models of SCA2 and SCA3 leads to a reduction in ataxin-2 and ataxin-3 aggregation. G3BP1 lentiviral delivery reduces motor deficits and neuropathology in preclinical models, suggesting that G3BP1 may be a potential therapeutic target for polyQ disorders. Polyglutamine diseases are a group of neurodegenerative disorders caused by an abnormal expansion of CAG repeat tracts in the codifying regions of nine, otherwise unrelated, genes. While the protein products of these genes are suggested to play diverse cellular roles, the pathogenic mutant proteins bearing an expanded polyglutamine sequence share a tendency to self-assemble, aggregate and engage in abnormal molecular interactions. Understanding the shared paths that link polyglutamine protein expansion to the nervous system dysfunction and the degeneration that takes place in these disorders is instrumental to the identification of targets for therapeutic intervention. Among polyglutamine diseases, spinocerebellar ataxias (SCAs) share many common aspects, including the fact that they involve dysfunction of the cerebellum, resulting in ataxia. Our work aimed at exploring a putative new therapeutic target for the two forms of SCA with higher worldwide prevalence, SCA type 2 (SCA2) and type 3 (SCA3), which are caused by expanded forms of ataxin-2 (ATXN2) and ataxin-3 (ATXN3), respectively. The pathophysiology of polyglutamine diseases has been described to involve an inability to properly respond to cell stress. We evaluated the ability of GTPase-activating protein-binding protein 1 (G3BP1), an RNA-binding protein involved in RNA metabolism regulation and stress responses, to counteract SCA2 and SCA3 pathology, using both in vitro and in vivo disease models. Our results indicate that G3BP1 overexpression in cell models leads to a reduction of ATXN2 and ATXN3 aggregation, associated with a decrease in protein expression. This protective effect of G3BP1 against polyglutamine protein aggregation was reinforced by the fact that silencing G3bp1 in the mouse brain increases human expanded ATXN2 and ATXN3 aggregation. Moreover, a decrease of G3BP1 levels was detected in cells derived from patients with SCA2 and SCA3, suggesting that G3BP1 function is compromised in the context of these diseases. In lentiviral mouse models of SCA2 and SCA3, G3BP1 overexpression not only decreased protein aggregation but also contributed to the preservation of neuronal cells. Finally, in an SCA3 transgenic mouse model with a severe ataxic phenotype, G3BP1 lentiviral delivery to the cerebellum led to amelioration of several motor behavioural deficits. Overall, our results indicate that a decrease in G3BP1 levels may be a contributing factor to SCA2 and SCA3 pathophysiology, and that administration of this protein through viral vector-mediated delivery may constitute a putative approach to therapy for these diseases, and possibly other polyglutamine disorders.pt_PT
dc.description.sponsorshipPPBI-POCI-01-0145-FEDER-022122pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1093/brain/awac473pt_PT
dc.identifier.issn0006-8950
dc.identifier.urihttp://hdl.handle.net/10400.1/19336
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Presspt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectG3BP1pt_PT
dc.subjectStress granulespt_PT
dc.subjectSpinocerebellar ataxiapt_PT
dc.subjectNeurodegenerationpt_PT
dc.titleThe stress granule protein G3BP1 alleviates spinocerebellar ataxia-associated deficitspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.titleBrainpt_PT
person.familyNameKoppenol
person.familyNameVieira da Conceição
person.familyNameTorquato Afonso
person.familyNameda Silva
person.familyNameAntunes Codêsso
person.familyNameVilhena Catarino Brito
person.familyNameMarcelo
person.familyNameAlbuquerque Andrade de Matos
person.familyNameNóbrega
person.givenNameRebekah
person.givenNameAndré Filipe
person.givenNameInês
person.givenNameJoana Pinto
person.givenNameJosé Miguel
person.givenNameDavid
person.givenNameAdriana
person.givenNameCarlos Adriano
person.givenNameClévio
person.identifier.ciencia-idF710-8071-CA06
person.identifier.ciencia-id9318-BAE4-B025
person.identifier.ciencia-id9D1C-5F50-904E
person.identifier.ciencia-id7918-F771-8F47
person.identifier.ciencia-id7613-00C2-1621
person.identifier.ciencia-idDC14-C299-222A
person.identifier.ciencia-idC510-7F41-BAF8
person.identifier.orcid0000-0002-1892-8670
person.identifier.orcid0000-0002-9348-3560
person.identifier.orcid0000-0003-1346-6777
person.identifier.orcid0000-0002-7706-1544
person.identifier.orcid0000-0002-2726-9347
person.identifier.orcid0000-0002-7327-0170
person.identifier.orcid0000-0002-9019-7569
person.identifier.orcid0000-0002-8312-5292
person.identifier.ridM-6047-2013
person.identifier.scopus-author-id24473454000
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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