Abstract
Alpha-synuclein (α-Syn) aggregation into oligomers and fibrils is associated with dopaminergic neuron loss occurring in Parkinson’s disease (PD) pathogenesis. Compounds that modulate α-Syn aggregation and interact with preformed fibrils/oligomers and convert them to less toxic species could have promising applications in the drug development efforts against PD. Curcumin is one of the Asian food ingredient which showed promising role as therapeutic agent against many neurological disorders including PD. However, the instability and low solubility makes it less attractive for the drug development. In this work, we selected various curcumin analogs and studied their toxicity, stability and efficacy to interact with different α-Syn species and modulation of their toxicity. We found a subset of curcumin analogs with higher stability and showed that curcumin and its various analogs interact with preformed fibrils and oligomers and accelerate α-Syn aggregation to produce morphologically different amyloid fibrils in vitro. Furthermore, these curcumin analogs showed differential binding with the preformed α-Syn aggregates. The present data suggest the potential role of curcumin analogs in modulating α-Syn aggregation.
Highlights
Α-synuclein (α-Syn) is a 140 amino acid residue protein (~14 kDa) expressed at high levels in neurons[1,2]
In order to alter the hydrophobicity of the analogs, the compounds were selected in such a way that hydroxyl group of curcumin was replaced by −OMe (C2, C4 and C5) and −OCH2Ph (C6) groups (Fig. 1)
As it was shown that the free hydroxyl groups of curcumin attached to the aromatic ring are modified by liver, kidney, and intestinal mucosa, produces curcumin glucuronide and curcumin sulfate, which results in low bioactivity[34,35,36], we expect that the selected analogs (−OH substituted with −OMe and −OCH2Ph) might show higher bioactivity
Summary
Α-synuclein (α-Syn) is a 140 amino acid residue protein (~14 kDa) expressed at high levels in neurons[1,2]. The α-Syn, during amyloid aggregation undergoes structural assembly from monomeric to fibrillar states through oligomeric intermediates Both in vitro as well as in vivo studies suggest that the soluble, oligomeric forms of α-Syn are potent neurotoxic species responsible for the neuronal injury and death of neurons in PD10–12. Molecules that inhibit the toxicity of oligomers either by reducing their formation or by converting them to less-toxic or non-toxic state would be an effective agent for the drug development against PD13–15 Based on this idea, several researchers have searched for chemically synthesized or naturally existing small molecules acting as inhibitors of α-Syn fibrilogenesis[14,16,17,18,19,20,21].
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