Abstract
Mutations in the HTT gene, consisting of expansion of CAG triplets, cause the Huntington’s disease (HD), one of the major neurodegenerative disorders. Formation of aggregates of mutant huntingtin (mHTT, the product of the mutant HTT gene) leads to cellular dysfunctions, and subsequent neurodegeneration which manifest clinically as motor abnormalities and cognitive deficits. We recently used immortalized HEK-293 cells expressing the 1st exon of the mutant HTT gene as a cellular model of HD, and showed that the stimulation of autophagy by genistein corrected the mutant phenotype. However, effects of genistein on HD patient-derived cells remained unknown. In this report, we demonstrated that genistein also instigated degradation of mHTT in fibroblasts derived from HD patients. This was assessed as a significant decrease in the levels of HTT in HD fibroblasts measured by Western-blotting, and the disappearance of intracellular mHTT aggregates in cells observed by fluorescent microscopy. Fibroblasts derived from control persons were not affected by genistein treatment. These results indicate that genistein can improve HD phenotype in patient-derived cells, and substantiates the need for further studies of this isoflavone as a potential therapeutic agent.
Highlights
Huntington’s disease (HD) is an autosomal dominant genetic disorder which is manifested clinically by specific symptoms including chorea, psychiatric disturbances and cognitive decline (Morreale 2015)
HD is caused by mutations in the HTT gene, coding for huntingtin (HTT), which result in the expansion of CAG repeats (Morreale 2015)
Psychiatric features were assessed by the Clinical Global Impressions scale (CGI), and the functional assessment was measured by the Total Functional Capacity scale (TFC), as described previously (Jędrak et al 2018)
Summary
Huntington’s disease (HD) is an autosomal dominant genetic disorder which is manifested clinically by specific symptoms including chorea, psychiatric disturbances and cognitive decline (Morreale 2015). This neurodegenerative disease is fatal, as no effective treatments are currently available (Shannon and Fraint 2015). HD is caused by mutations in the HTT gene, coding for huntingtin (HTT), which result in the expansion of CAG repeats (Morreale 2015) This expansion results in the formation of a long tract of glutamine residues (the polyQ tract) in the mutant huntingtin protein (mHTT). Genistein (trihydroxyisoflavone or 5, 7-dihydroxy-3- (4hydroxyphenyl)-4H-1-benzopyran-4-one), a potent autophagy stimulator, might be a putative drug for the treatment of neurodegenerative diseases, because it crosses the blood-brain-barrier, and is safe when administered even at high doses (like 150 mg/kg/day) for several months to animals and humans
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