Abstract
Polyglutamine (polyQ) diseases are a group of 9 rare neurodegenerative disorders caused by an abnormal expansion of the CAG trinucleotide in the codifying regions of the respective disease-associated gene. The trinucleotide abnormal expansion leads to the translation of a protein containing an overexpanded tract of glutamines. PolyQ mutant proteins undergo a gain of toxic function disrupting normal cellular pathways leading to neuronal death and, consequently, leading to selective neurodegeneration of specific brain regions. Spinocerebellar ataxia (SCA) 2 and SCA3 (also known as Machado-Joseph disease) are two different polyQ diseases in which the ataxin-2 and ataxin-3 proteins, respectively, bear abnormally long polyQ tracts. Until now, there is no treatment for these fatal diseases or therapies that could delay the normal pathologic progression. Stress granules (SGs) are important structures formed in response to cellular stress, having an important role in mRNA triage. A core component of SGs is the RNA-binding protein (RBP) Ras GTPase-activating protein-binding protein 1 (G3BP1), which is also implicated in the SGs assembly. Furthermore, G3BP1 is known to have endoribonuclease activity and an important role in modulating RNA metabolism. In this study, we showed that G3BP1 is decreased in context of SCA2 and SCA3 disease. For that, we assessed whether restoring the expression levels of G3BP1 might positively impact the SCA2 and SCA3 pathology. We showed that gene delivery of G3BP1 in two distinct lentiviral mouse model of SCA2 and SCA3 was able to i) reduce the number of aggregates and ii) reduce the loss of neuronal marker associated with the mutant toxic proteins. Importantly, in a polyQ transgenic mouse model, lentiviral delivery of G3BP1 in the cerebellum was able to i) preserve the number of Purkinje cells, ii) reduce the number of HA-ataxin-3 and, importantly iii) improve the motor performance, balance and coordination. Additionally, we identify the nuclear transport nuclear transport factor 2-like (NTF2-like) domain and the ser149 phosphorylation site of G3BP1 as a key players in the reduction of mutant ataxin-2 and ataxin-3 levels and aggregation. Altogether these results showed that gene delivery of G3BP1 is able of mitigating the disease-associated phenotype in SCA2 and SCA3 disease, in three different disease mouse models. Therefore, this study suggests G3BP1 as a novel therapeutic target for SCA2 and SCA3 diseases.
Subconjunctival gene delivery of the transcription factor GA-binding protein delays corneal neovascularization in a mouse model
