Abstract
Accumulation of misfolded proteins in the brain is a common hallmark of most age-related neurodegenerative diseases. Previous studies from our group identified the presence of anti-inflammatory and antioxidant compounds in leaves derived from the Chilean berry Ugni molinae (murtilla), in addition to show a potent anti-aggregation activity in models of Alzheimer´s disease. However, possible beneficial effects of berry extracts of murtilla was not investigated. Here we evaluated the efficacy of fruit extracts from different genotypes of Chilean-native U. molinae on reducing protein aggregation using cellular models of Huntington´s disease and assess the correlation with their chemical composition. Berry extraction was performed by exhaustive maceration with increasing-polarity solvents. An unbiased automatic microscopy platform was used for cytotoxicity and protein aggregation studies in HEK293 cells using polyglutamine-EGFP fusion proteins, followed by secondary validation using biochemical assays. Phenolic-rich extracts from murtilla berries of the 19-1 genotype (ETE 19-1) significantly reduced polyglutamine peptide aggregation levels, correlating with the modulation in the expression levels of autophagy-related proteins. Using LC-MS and molecular network analysis we correlated the presence of flavonoids, phenolic acids, and ellagitannins with the protective effects of ETE 19-1 effects on protein aggregation. Overall, our results indicate the presence of bioactive components in ethanolic extracts from U. molinae berries that reduce the load of protein aggregates in living cells.
Highlights
The accumulation of misfolded proteins is the hallmark pathological feature of several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and polyglutamine disorders, which among others are referred to as protein misfolding disorders (PMDs) [1]
In this study we have identified significant differences in the neuroprotective properties of acetone extracts (ACEs) and ethanolic extracts (ETEs) obtained from U. molinae fruits of different genotypes
ETE 19–1 extracts had a potent activity over the abnormal protein aggregation on two different cellular models of HD, which might be mediated, in part, by the modulation of the proteostasis network
Summary
The accumulation of misfolded proteins is the hallmark pathological feature of several neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and polyglutamine (polyQ) disorders, which among others are referred to as protein misfolding disorders (PMDs) [1]. Multiple pathways have been identified as part of the pathophysiological process of PMDs, effective treatments for these diseases are still unavailable. Numerous studies have provided associations between the consumption of polyphenolic-rich foods, including berries, and the reduction in the long-term risk to develop neurodegenerative diseases, among other chronic pathologies [4]. The possible mechanisms involved in the neuroprotective effects of polyphenols and polyphenolic-rich extracts include direct interactions with key amino acid residues present in misfolded proteins and aggregates [5, 6], the scavenging of reactive oxygen species (ROS) [9], modulation of antioxidant enzymes [9], and the regulation of cellular pathways involved in protein quality control, such as autophagy [16] and the ubiquitin-proteasome system [17]. Intervention strategies based on the use of natural compounds may offer interesting therapeutic avenues to treat neurodegenerative diseases
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