The stress granule protein G3BP1 alleviates spinocerebellar ataxia-associated deficits


 Polylgutamine (polyQ) diseases are a group of neurodegenerative disorders caused by 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 cell roles, the pathogenic mutant proteins bearing an expanded polyQ sequence share a tendency to self-assemble, aggregate, and engage in abnormal molecular interactions. Understanding the shared paths that link polyQ protein expansion to the nervous system dysfunction and degeneration that takes place in these disorders is instrumental for identifying targets for therapeutic intervention. Among polyQ diseases, spinocerebellar ataxias (SCAs) share many common aspects, including the fact that they involve the functional compromise of the cerebellum, resulting in the hallmark ataxic signs. Our work aimed at exploring a putative new therapeutic target for the two forms of SCA with higher worldwide prevalence, spinocerebellar ataxias type 2 (SCA2) and type 3 (SCA3), which are caused by expanded forms of ataxin-2 (ATXN2) and ataxin-3 (ATXN3), respectively. PolyQ disease pathophysiology has been described to involve an inability to properly respond to cell stress. Taking into consideration, we evaluated the ability of GTPase-activating protein-binding protein 1 (G3BP1), an RNA-binding protein involved in RNA metabolism regulation and in 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 polyQ 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 SCA2 and SCA3 patients, suggesting that G3BP1 function is compromised in the context of these diseases. In lentiviral models of SCA2 and SCA3, G3BP1 overexpression not only decreased protein aggregation but also contributed to the preservation of neuronal cells. Finally, in a SCA3 transgenic mouse model with a severe ataxic phenotype, G3BP1 lentiviral delivery to the cerebellum led to amelioration of several motor behavioral deficits. Overall, our results suggest that a decrease in G3BP1 levels may be a component of 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 polyQ disorders.