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Title: The stress granule protein G3BP1 alleviates spinocerebellar ataxia-associated deficits
Authors: Koppenol, Rebekah
Conceição, André 
Afonso, Inês T.
Afonso-Reis, Ricardo
Costa, Rafael G.
Tomé, Sandra 
Teixeira, Diogo 
da Silva, Joana Pinto
Codêsso, José Miguel 
Brito, David V. C.
Mendonça, Liliana 
Marcelo, Adriana 
Almeida, Luís Pereira de 
Matos, Carlos A.
Nóbrega, Clévio 
Keywords: G3BP1; stress granules; spinocerebellar ataxia; neurodegeneration
Issue Date: 1-Jun-2023
Publisher: Oxford University Press
Project: This work was funded by the Portuguese Science and Technology Foundation (FCT) project (ALG-01- 0145-FEDER-29480) ‘SeGrPolyQ’, with CRESC ALGARVE 2020 cofunding and the French Muscular Dystrophy Association (AFM-Téléthon) project #22424. SFRH/BD/ 148533/2019 Rebekah Koppenol’s PhD Fellowship, DFA/BD/7892/ 2020 André Conceição’s PhD Fellowship and SFRH/BD/133192/ 2017 Adriana Marcelo’s PhD Fellowship were funded by FCT. 
Serial title, monograph or event: Brain
Volume: 146
Issue: 6
Abstract: 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.
ISSN: 0006-8950
DOI: 10.1093/brain/awac473
Rights: openAccess
Appears in Collections:FFUC- Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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