Ellagic Acid Inhibits α-Synuclein Aggregation at Multiple Stages and Reduces Its Cytotoxicity

Abstract

α-Synuclein is a natively unfolded protein and its deposition in the Lewy body and Lewy neurites in the substantia nigra region of the brain is linked to Parkinson's disease (PD). The molecular mechanisms of α-synuclein aggregation and its clearance have not been well understood. Until now, several strategies have been designed to inhibit α-synuclein aggregation and related cytotoxicity. Polyphenols, small molecules, synthetic peptides, and peptide-derived molecules have been considered as potential candidates that inhibit α-synuclein oligomerization and its fibrillation, and a few of them are in clinical trials. We have identified a polyphenolic compound ellagic acid (EA) that inhibits α-synuclein aggregation. Our results demonstrated that EA inhibits primary nucleation, seeded aggregation, and membrane-induced aggregation. The cytotoxicity of α-synuclein oligomers and fibers treated with EA has been investigated and we found that EA treated oligomers and fibrils showed reduced cytotoxicity. Additionally, we also observed inhibition of membrane binding of αsynuclein by EA in SH-SY5Y cells. In conclusion, the present study suggests that small molecules such as ellagic acid have antiamyloidogenic properties and may have therapeutic potential for Parkinson's disease and other proteinopathies.

Ellagic Acid Modulates Uninduced as well as Mutation and Metal-Induced Aggregation of α-Synuclein: Implications for Parkinson’s Disease

“…Yan et al have revealed the effect of EA on prion protein fibrillization . Recently, Kumar et al indicated that EA inhibits aggregation of wild-type αS at multiple stages . However, the present study aimed was to systematically assess the modulatory effect of EA against uninduced (wild-type αS) as well as mutation (A53T and E46K) and metal-induced aggregation of αS.…”

“…29 Recently, Kumar et al indicated that EA inhibits aggregation of wild-type αS at multiple stages. 30 However, the present study aimed was to systematically assess the modulatory effect of EA against uninduced (wild-type αS) as well as mutation (A53T and E46K) and metal-induced aggregation of αS. Hence, this study reveals that EA could be a potential agent against familial cases as well as sporadic cases of Parkinson's disease.…”

pH Effects Can Dominate Chemical Shift Perturbations in 1H,15N-HSQC NMR Spectroscopy for Studies of Small Molecule/α-Synuclein Interactions

“…NMR spectroscopy has been successfully employed in several drug discovery campaigns for structured protein targets but has found limited success in the investigation of IDPs . There have been several NMR studies that explore small-molecule binding to mature aSyn fibrils , as well as a few reportsusing 1 H, 15 N-HSQC NMR spectroscopy (HSQC)where small molecules (including epigallocatechin gallate (EGCG), Baicalin, and dopamine (DOPA)) have been shown to engage monomeric or low-molecular-weight aSyn species. − …”

Unravelling the destabilization potential of ellagic acid on α-synuclein fibrils using molecular dynamics simulations

“…Various peptides, 14 nanoparticles, 15 small molecules, 16 antibodies, 17 and polymers 18 blocked α-Syn aggregation, destabilized pre-existing α-Syn fibrils, and suppressed their growth. Amidst these inhibitors, small molecules originating from natural sources such as epigallocatechin gallate (EGCG), 16 b ellagic acid (EA), 19 curcumin, 20 rosmarinic acid, 21 dihydromyricetin (DHM), 22 brazilin, 23 and baicalein, 24,25 have gained special interest because of their low toxicity and high availability.…”