I015 Autophagy stimulation corrects symptoms of Huntington disease in cellular and animal models of the disease

<h3>Background</h3> Previous studies demonstrated that genistein (4’,5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4 H-1-benzopyran-4-one) could cause a significant decrease in number and size of aggregates of mutant huntingtin in cellular models of the Huntington disease (HD) due to stimulation of the autophagy process.^{1 2} <h3>Aims</h3> To test if genistein can improve symptoms in an animal model of HD, and to elucidate a molecular mechanism of autophagy stimulation by genistein. <h3>Methods/Techniques</h3> The R6/1 mouse model of HD was used. In experiments with cell cultures, fibroblasts derived from HD patients were employed. Protein levels were estimated by Western-blotting. Fluorescence microscopy with specific antibodies was used to visualize proteins in cells. Gene expression silencing was performed using siRNAs. A battery of behavioural tests was performed to assess functions of the central nervous system in mice. <h3>Results/Outcome</h3> We demonstrate that stimulation of autophagy by genistein (administered orally at the dose of 150 mg/kg/day) led to reductions of levels of mutated HTT in brains of HD mice. Moreover, correction of the animal behaviour was found in a battery of cognitive, anxiety and motor tests. Such corrections were evident in both males and females. Moreover, genistein was effective when the treatment was initiated before the appearance of symptoms, as well as when the compound was administered after symptoms had developed in the animals. Molecular studies indicated that genistein activated the autophagy process through the FOXO3-depement pathway. <h3>Conclusions</h3> Treatment of pre- or post-symptomatic animals with genistein at the dose of 150 mg/kg/day can prevent or correct symptoms of HD in the R6/1 model of this disease, respectively. The mechanism of genistein-mediated prevention/correction of HD symptoms is based on FOXO3-depement stimulation of autophagy. <h3>References</h3> Pierzynowska K, <i>et al. Neuromolecular Med</i>. 2018;<b>20</b>:112-123. Pierzynowska K, et al. <i>Metab Brain Dis.</i> 2019;<b>34</b>:715-720.