Astragaloside IV Reduces Mutant Ataxin-3 Levels and Supports Mitochondrial Function in Spinocerebellar Ataxia Type 3

Abstract

Abstract This study investigated the effects of astragaloside IV (AST) on the neurodegenerative disease of spinocerebellar ataxia type 3 (SCA3). Human neuroblastoma SK-N-SH cells expressing mutant ataxin-3 protein with 78 CAG repeats (MJD78) were used as an in vitro model, and SCA3 transgenic mice harboring an allele with a pathological polyglutamine tract with expanded 84 CAG repeats (SCA3 84Q) were used as an in vivo model. Protein expression analysis revealed that AST treatment reduced mutant ataxin-3 protein expression and aggregation via increased the autophagic flux in the MJD78 cells. Oxidative stress levels were elevated in the MJD78 cells but were reduced after AST treatment, which also increased antioxidant capacity; these findings were obtained using flow cytometry and antioxidant enzyme activity assay. Furthermore, treatment with AST ameliorated mitochondrial dysfunction in the MJD78 cells, including that related to mitochondrial membrane potential, respiration, and mitochondrial dynamics. Additionally, AST administration improved motor function and provided protection against Purkinje cell loss in the cerebellum of the SCA3 84Q mice. In conclusion, AST administration increase the capability of antioxidants and reduced either cellular or mitochondrial oxidative stress and improve the process of mitochondrial quality control by fusion, fission, and autophagy. Summarizing, aforementioned mechanisms reduced intracellular mutant ataxin-3 protein aggregation to achieve therapeutic effectiveness in the SCA3 model.