Stress granules in Polyglutamine diseases: new targets for therapeutic intervention?

• Main Author: Marcelo, Adriana Isabel do Vale
• Publication Date: 2022
• Language: eng
• Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Download full: http://hdl.handle.net/10400.1/18477
• topic: Doenças de poliglutaminas; Ataxia espinocerebelosa do tipo 3; Ataxia espinocerebelosa do tipo 2; Grânulos de stress; Componentes dos grânulos de stress; Modelos de ratinho de doenças

Polyglutamine (PolyQ) diseases are a group of hereditary and incurable neurodegenerative pathologies, caused by abnormal expansion of CAG trinucleotide repeats in the disease-causing genes. In these disorders, the formation of toxic aggregated species from the expanded protein leads to dysfunction of several biological systems, ultimately resulting in neuronal degeneration and death widespread across different brain regions. Dysfunction of cellular pathways also correlates with stress responses, such as the formation of stress granules (SGs). Recently, multiple evidence suggested that SGs and its components play a role in the pathogenesis of PolyQ diseases. Therefore, the general goal of this project was to clarify the SGs role in the context of PolyQ diseases pathogenesis, trying to identify new pathways and targets for a therapeutic intervention, using spinocerebellar ataxia type 3 (SCA3) and type 2 (SCA2) as PolyQ disease models. We found that several SGs components have their gene expression levels altered in these two diseases, including regulated heat stable protein 1 (CARHSP1) and Pumilio homolog 1 (PUM1), which have their levels upregulated in SCA3 and SCA2 diseases. We found that the downregulation of CARHSP1 resulted in reduced mutant protein aggregation in SCA3 cellular and mouse models, as well as amelioration of motor and neuropathological abnormalities. On the other hand, knockdown of PUM1 levels led to increased aggregation of polyQ-expanded protein, as well as worsening of motor deficits in mouse models of SCA3 disease. We further assessed the downregulation of CARHP1 in a novel striatal lentiviral mouse of SCA2, although no alterations in neuropathological features were observed. Overall, our study contributes to the putative involvement of SGs in PolyQ disease and showed that the modulation of CARHSP1 SGs component could be potential therapeutic approach for SCA3 disease. Future studies are needed to fully understand SGs and its components importance in the context of PolyQ and other neurodegenerative diseases.