Correction of Huntington’s disease phenotype by genistein-induced autophagy in the cellular model
Karolina Pierzynowska , Lidia Gaffke , Aleksandra Hać , Jagoda Mantej , Natalia Niedziałek , Joanna Brokowska , Grzegorz Węgrzyn
AbstractHuntington’s disease (HD) is a monogenic disorder, caused by mutations in the HTT gene which result in expansion of CAG triplets. The product of the mutated gene is misfolded huntingtin protein that forms aggregates leading to impairment of neuronal function, neurodegeneration, motor abnormalities and cognitive deficits. No effective cure is currently available for HD. Here we studied effects of genistein (trihydroxyisoflavone) on a HD cellular model consisting of HEK-293 cells transfected with a plasmid bearing mutated HTT gene. Both level of mutated huntingtin and number of aggregates were significantly decreased in genistein-treated HD cell model. This led to increased viability of the cells. Autophagy was up-regulated while inhibition of lysosomal functions by chloroquine impaired the genistein-mediated degradation of the mutated huntingtin aggregates. Hence, we conclude that through stimulating autophagy, genistein removes the major pathogenic factor of HD. Prolonged induction of autophagy was suspected previously to be risky for patients due to putative adverse effects; however, genistein has been demonstrated recently to be safe and suitable for long-term therapies even at doses as high as 150 mg/kg/day. Therefore, results presented in this report provide a basis for the use of genistein in further studies on development of the potential treatment of HD.
|Journal series||Neuromolecular Medicine, ISSN 1535-1084|
|Publication size in sheets||0.55|
|Keywords in English||Huntington’s disease, genistein, autophagy, protein aggregates|
|License||Other; published final; ; with publication|
|Score|| = 30.0, 03-04-2018, ArticleFromJournal|
= 35.0, 03-04-2018, ArticleFromJournal
|Publication indicators||: 2016 = 3.287 (2) - 2016=3.328 (5)|
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.