A natural small molecule‐mediated inhibition of alpha‐synuclein aggregation leads to neuroprotection in Caenorhabditis elegans

Small molecules are being explored intensively for their applications as therapeutic molecules in the management of metabolic and neurological disorders. The natural small molecules can inhibit protein aggregation and underlying cellular pathogenesis of neurodegenerative diseases involving multi‐factorial mechanisms of action. Certain natural small molecular inhibitors of pathogenic protein aggregation are highly efficient and have shown promising therapeutic potential. In the present study, Shikonin (SHK), a natural plant‐based naphthoquinone has been investigated for its aggregation inhibition activity against α‐synuclein (α‐syn) and the neuroprotective potential in Caenorhabditis elegans (C. elegans). SHK significantly inhibited aggregation of α‐syn at sub‐stochiometric concentrations, delayed the linear lag phase and growth kinetics of seeded and unseeded α‐syn aggregation. The binding of SHK to the C‐terminus of α‐syn maintained α‐helical and disordered secondary structures with reduced beta‐sheet content and complexity of aggregates. Further, in C. elegans transgenic PD models, SHK significantly reduced α‐syn aggregation, improved locomotor activity and prevented dopaminergic (DA) neuronal degeneration, indicating the neuroprotective role of SHK. The present study highlights the potential of natural small molecules in the prevention of protein aggregation that may further be explored for their therapeutic efficacy in the management of protein aggregation and neurodegenerative diseases. In this study, a small natural molecule shikonin has been explored for its anti‐aggregation and neuroprotective activities. Shikonin significantly inhibited α‐syn aggregation at equimolar and sub‐stochiometric concentrations by stabilizing the monomers, increasing lag time and delaying elongation of α‐syn fibrils. Also, in C. elegans PD models, shikonin showed neuroprotection and rescued neuronal degeneration by reducing α‐syn aggregation, improving locomotor activity and preventing dopaminergic neuronal degeneration. The present study highlights the role of natural small molecules in the prevention of protein aggregation, that may further be explored for their therapeutic potential.