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L11 A novel approach for treatment of huntington’s disease by genistein-mediated stimulation of autophagy
  1. Karolina Pierzynowska,
  2. Aleksandra Hac,
  3. Sylwia Baranska,
  4. Grzegorz Wegrzyn
  1. Department of Molecular Biology, University of Gdansk, Gdansk, Poland

Abstract

Background Expansions of CAG codons in the first exon of the HTT gene, encoding huntingtin, result in production of the protein that forms aggregates in cells, being the cause of cellular dysfunctions. Genistein (5, 7-dihydroxy-3- (4-hydroxyphenyl)−4H-1-benzopyran-4-one) is a naturally occurring isoflavone that has a number of biological activities. Recent studies performed by our group (Moskot et al. 2014, J. Biol. Chem. 289:17054–69; Moskot et al. 2015, Sci. Rep. 5:9378) indicated that genistein stimulates biogenesis of lysosomes and production of lysosomal hydrolases.

Aims The aim of this work was to determine if genistein can cause effective degradation of huntingtin’s aggregates, and if yes, what is the molecular mechanism of this phenomenon.

Methods Human embryonic kidney (HEK) cells were transfected with a plasmid expressing the first exon of huntingtin which codes for 74 glutamine repeats (pEGFP-Q74). The analyses were performed by using fluorescence microscopy, Western-blotting, and cell survival assays.

Results We found that the presence of genistein in culture medium resulted in a significant decrease in the number of mutant huntingtin aggregates, as well as in the reduction of their volume. Biochemical analyses indicated that the amount of mutant huntingtin decreased considerably in genistein-treated cells relative to controls. Under these conditions, survival of such cells increased by a few times. Genistein was able to stimulate the process of autophagy, as demonstrated by an increased level of the LC3-II protein in cells in the presence of this isoflavone in the culture medium. Inhibition of lysosomal functions resulted in inability of genistein to stimulate huntingtin degradation.

Conclusions Genistein stimulates the autophagy process which leads to degradation of mutant huntingtin. Therefore, one might suggest that genistein could be considered as a novel compound inhibiting the Huntington’s disease.

  • Genistein
  • autophagy
  • huntingtin degradation

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