Correction of Huntington’s Disease Phenotype by Genistein-Induced Autophagy in the Cellular Model

Abstract

Huntington’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.

Mucopolysaccharidosis and Autophagy: Controversies on the Contribution of the Process to the Pathogenesis and Possible Therapeutic Applications

“…This stimulation is due to enhanced synthesis of transcription factor EB (TFEB), the master regulator of lysosomal biogenesis, as well as its activation due to inhibition of activity of the mTOR kinase (Moskot et al 2014). Therefore, genistein can be considered an autophagy stimulator which has been demonstrated experimentally (Pierzynowska et al 2018b).…”

“…These include misfolded protein aggregates which are primary pathogenic agents in different diseases, including the most common severe neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, and Huntington's disease. In fact, activation of autophagy has recently been proposed as a promising strategy for development of drugs for such neurodegenerative diseases (Pierzynowska et al 2018a(Pierzynowska et al , 2018b. There are some molecules that are not only autophagy stimulators, but also can cross the blood-brain barrier and appear to be safe in a long-term treatment of patients, which make them promising candidates for drugs, as discussed recently (Pierzynowska et al 2018a).…”

Molekularne mechanizmy działania genisteiny w świetle terapii chorób genetycznych i immunologicznych

“…Inkubacja komórek eksprymujących zmutowany i prawidłowy wariant HTT w obecności genisteiny wykazała zależny od stężenia spadek poziomu mHTT przy jednoczesnym utrzymaniu stałego poziomu prawidłowej HTT. Nie tylko rozpuszczalna forma białka, ale też tworzone przez nią agregaty ulegają usunięciu w komórkach traktowanych opisywanym izoflawonem [79]. Działanie to występuje dzięki indukcji procesu autofagii, jednej z głównych dróg usuwania makrocząsteczek w komórkach [80] (Ryc.…”

“…Induktory procesu autofagii są potencjalnymi kandydatami jako leki głównie z powodu specyficzności tego procesu względem nieprawidłowych form białek (o czym świadczy m.in. stały poziom zdrowej formy HTT po traktowaniu genisteiną), gdyż prawidłowe ich formy pełnią w organizmie wiele ważnych funkcji [79].…”

Differential effects of various soy isoflavone dietary supplements (nutraceuticals) on bacterial growth and human fibroblast viability

“…Among these activities, some have been recognized as beneficial for human health, and particularly the following features were reported: antioxidative properties, implication in coronary heart disease prevention, hepatoprotective, anti-inflammatory, and anticancer functions, as well as antiviral and antimicrobial actions (Kumar & Pandey, 2013). Experimental studies indicated that flavonoids, especially isoflavones, can be also considered as drugs for some genetic diseases, particularly cystic fibrosis, mucopolysaccharidosis (reviewed in Wegrzyn, 2012;Wegrzyn et al, 2010), and Huntington's disease (Pierzynowska et al, 2018).…”