Snake venom-inspired novel peptides protect Caenorhabditis elegans against paraquat induced Parkinson's pathology

The in vivo protective mechanisms of two low molecular mass ([~]1.4 kDa) novel custom peptides (CPs) against paraquat (PT)-induced neurodegenerative dysfunction in the Caenorhabditis elegans model were deciphered. CPs prevent the PT binding to the nerve ring adjacent to the pharynx in C. elegans (N2 strain) by stable and high-affinity binding to the tyrosine-protein kinase receptor CAM-1, resulting in significant inhibition of PT-induced toxicity by reducing enhanced reactive oxygen species production, mitochondrial membrane depolarization, and chemosensory dysfunction. The CPs inhibited PT-induced dopaminergic (DAergic) neuron degeneration and alpha-synuclein aggregation, the hallmarks of Parkinsons Disease, in transgenic BZ555 and NL5901 strains of C. elegans. The transcriptomic, functional proteomics, and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses show that CPs prevented the increased expression of the genes involved in the skn-1 downstream pathway, thereby restoring PT-mediated oxidative stress, apoptosis, and neuronal damage in C. elegans. The CPs ability to repair PT-induced damage was demonstrated by a network of gene expression profiles illustrating the molecular relationships between the regulatory proteins. Further, CPs (10 mg/kg, parental route) did not show toxicity or induce inflammatory mediators in the mouse model.