GST-4-Dependent Suppression of Neurodegeneration in C. elegans Models of Parkinson's and Machado-Joseph Disease by Rapeseed Pomace Extract Supplementation.

Franziska Pohl,Andreia Teixeira-Castro,Victoria Lindsay,Wendy Russell,Juliana Fiúza-Fernandes,Paul Kong Thoo Lin,Giovanna Bermano,Marta Daniela Costa,Marie Goua,Patrícia Maciel

doi:10.3389/fnins.2019.01091

Franziska Pohl, Andreia Teixeira-Castro + Show 8 more

Open Access

https://doi.org/10.3389/fnins.2019.01091

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Abstract

Genetic mutations and aging-associated oxidative damage underlie the onset and progression of neurodegenerative diseases, like Parkinson’s disease (PD) and Machado-Joseph disease (MJD). Natural products derived from plants have been regarded as important sources of novel bioactive compounds to counteract neurodegeneration. Here, we tested the neuroprotective effect of an ethanolic extract of rapeseed pomace (RSP), a rapeseed (canola) oil production by-product, in C. elegans models of MJD and PD. The extract, containing sinapine and other phenolics, restored motor function of mutant ataxin-3 (ATXN3) animals (MJD) and prevented degeneration of dopaminergic neurons in one toxin-induced and two genetic models of PD. Whole-organism sensors of antioxidant and xenobiotic response activation revealed the induction of phase II detoxification enzymes, including glutathione S- transferase (GST-4) upon RSP extract supplementation. Furthermore in vivo pharmacogenetic studies confirmed gst-4 is required for the therapeutic effect of RSP extract in the two disease models. The results suggest that GST-4-mediated antioxidant pathways may constitute promising therapeutic co-targets for neurodegenerative diseases and confirm the utility of searching for bioactive compounds in novel sources, including food and agricultural waste/by-products, such as RSP.

Highlights

The number of people affected by neurodegenerative diseases has been increasing significantly over the last few decades, due to the ever-growing world population and an increase in life expectancy
rapeseed pomace (RSP) extract safety concentration range in C. elegans was determined by the food clearance assay (Voisine et al, 2007)
A compound is considered safe to C. elegans if it causes no changes in animal growth, survival, and number of offspring, which can be measured indirectly by determining the rate of food consumption of the E. coli bacteria (OP50)

Summary

Introduction

The number of people affected by neurodegenerative diseases has been increasing significantly over the last few decades, due to the ever-growing world population and an increase in life expectancy. Drug discovery efforts are a priority (Joyner and Cichewicz, 2011; Ebrahimi and Schluesener, 2012) Many neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s as well as other polyglutamine diseases, including Machado-Joseph disease (MJD), or Spinocerebellar ataxia type 3 (SCA3) have in common their association with aging, protein aggregation and oxidative stress (Gandhi and Abramov, 2012; Kim et al, 2015). The involvement of oxidative stress in MJD is less well documented, it is thought that ATXN3 plays an important role in regulating the FOXO4-dependent antioxidant stress response via the manganese superoxide dismutase (SOD2), which is disrupted upon expression of the mutant protein This suggests that a decreased antioxidative capacity and an increased susceptibility toward oxidative stress contribute to neuronal cell death in MJD (Araujo et al, 2011). This suggests that approaches to improve the cellular antioxidant capacity could lead to effective therapeutics

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