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

Abstract

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.image

Aging and neurodegeneration: From molecular mechanisms to therapeutic interventions

“…Finally, two studies focus more directly on possible therapeutic interventions for neurodegeneration. Srivastava et al provide evidence for the effect of a natural small molecule on inhibiting α-synuclein aggregation, thereby leading to neuroprotection in the versatile model Caenorhabditis elegans (Srivastava et al, 2023).…”

Pharmacological inhibition of α-synuclein aggregation within liquid condensates

“…Since the kinetic network that describes the mechanism of aggregation of α-synuclein is the same along the deposition and condensation pathways 26 (Supplementary Fig. 1 ), one may explore whether compounds reported to inhibit the aggregation of α-synuclein along the deposition pathway 6 – 10 , 32 may also work along the condensation pathway. However, because the concentration in the condensates is up to three orders of magnitude higher than in the dilute phase 26 , compounds that inhibit α-synuclein aggregation along the deposition pathway may lose their potency in the condensates 33 .…”