Bioactive compounds of plants as modulators of heat stress and protein aggregation induced toxicity in the nematode Caenorhabditis elegans

The average global temperature increased by climate change represents a new environmental risk factor which influences people, animals and plants, in a complex interconnection that the One Health approach aims to address in order to promote global health. From the human health perspective, heat stress effects on neurotoxic protein aggregation, typical of several neurodegenerative diseases and, particularly, on a small family of abnormally long poly-glutamine (polyQ) repeats induced disorders, are still partially unknown. Simultaneously, plants respond to acute climate stressors enhancing their secondary metabolites production, known as beneficial in humans. This study investigates the protective and antioxidant potential against heat stress of several bioactive compounds of plants in Caenorhabditis elegans, thereafter focusing on erucin (ERN), an isothiocyanate naturally present in its oxidized form, sulforaphane, in broccoli, and in its precursor molecule, glucoerucin, in rocked salad leaves. Through the treatment of C.elegans strains expressing polyQ in different tissues, this research demonstrates that ERN protects from polyQ-induced toxicity both in standard and under heat stress conditions. Moreover, it evidences that ERN action is dependent on the catalytic subunit of AMP-activated protein kinase (aak-2/AMPKα2) and, downstream in this pathway, on the daf-16/FOXO transcription factor, since nematodes defective of aak-2/AMPKα2 and daf-16 did not respond to the treatment, respectively. Additionally, the treatment of C.elegans models of Parkinson’s Disease, affected by a different source of neurotoxicity than polyQ disorders, i.e by α-synuclein (α-syn) aggregates, evidences that ERN reduces α-syn-aggregates in standard conditions and improves the motility of worms even after heat stress. Taken together, these results demonstrate ERN modulation of heat stress and protein aggregates induced toxicity and, at least partially, the pathway involved in its mechanism of action in C. elegans, justifying further pre-clinical studies in mice models of protein aggregation to test whether it could represent a potential neuroprotective compound even in humans.