A phenolic-rich extract from Ugni molinae berries reduces abnormal protein aggregation in a cellular model of Huntington’s disease

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.

Phytochemicals Mediate Autophagy Against Osteoarthritis by Maintaining Cartilage Homeostasis

“…In recent years, researches have confirmed the beneficial effects of flavonoids to health, including their use in conditions related to autophagy, such as neurodegenerative diseases ( Dai et al, 2021a ; Pérez-Arancibia et al, 2021 ). A large number of experiments have shown that flavonoids and its derivatives can improve chondrocytes and thus combat against OA, which makes it possible to apply flavonoids in clinical studies ( Basu et al, 2018 ; Ansari et al, 2020 ).…”

Natural product-based pharmacological studies for neurological disorders

“…Arancibia et al discovered that extracts (phenolic rich) from murtilla berries of the 19-1 genotype significantly decreased peptide (polyglutamine) accumulation amounts, corresponding with the regulation in the expression patterns of proteins, which are related to autophagy and thus promising in HD therapy. Berries were extracted by exhaustive maceration with increasing polarity solvents ( Pérez-Arancibia et al, 2021 ).…”

Advances in Modeling Polyglutamine Diseases Using Genome Editing Tools

“…Additionally, the models explore genetic pathways and mechanisms underlying disease development such as expansions, aberrant splicing, repeat-associated non-AUG (RAN) translation and RNA frameshifting. By using methods such as lentiviral transduction, microinjection with mRNA and transposase-mediated recombination, transgenic models were generated in yeast [87,88], human embryonic kidney (HEK) 293T cells [89][90][91], C. elegans [92][93][94][95], D. melanogaster [96][97][98], zebrafish [99][100][101][102], the mouse [27,[103][104][105][106][107][108][109][110][111][112][113], rat [83,114], sheep [115], pig [116,117] and monkey [118][119][120][121]. Additionally, patient-derived cells were reprogrammed into iPSCs and used to model polyQ diseases [122][123][124][125][126][127][128].…”

“…Yet, though these models are easy to produce and maintain and provide a convenient basis for experiments, HEK-based models are simplified and lack a full genomic background of the promoter strength, or the full-length gene. HEK 293T cells with polyQ transgenes have been successfully used in drug-screening experiments [91] to analyze the molecular pathways and interactors involved in the pathogenesis of polyQ disease [89], as well as to study trinucleotide expansions [130]. An et al performed a comprehensive analysis of nuclease-based genomeediting methods in HEK 293F cells in 2014 [62].…”