Curcumin Modulates α-Synuclein Aggregation and Toxicity

Abstract

In human beings, Parkinson's disease (PD) is associated with the oligomerization and amyloid formation of α-synuclein (α-Syn). The polyphenolic Asian food ingredient curcumin has proven to be effective against a wide range of human diseases including cancers and neurological disorders. While curcumin has been shown to significantly reduce cell toxicity of α-Syn aggregates, its mechanism of action remains unexplored. Here, using a series of biophysical techniques, we demonstrate that curcumin reduces toxicity by binding to preformed oligomers and fibrils and altering their hydrophobic surface exposure. Further, our fluorescence and two-dimensional nuclear magnetic resonance (2D-NMR) data indicate that curcumin does not bind to monomeric α-Syn but binds specifically to oligomeric intermediates. The degree of curcumin binding correlates with the extent of α-Syn oligomerization, suggesting that the ordered structure of protein is required for effective curcumin binding. The acceleration of aggregation by curcumin may decrease the population of toxic oligomeric intermediates of α-Syn. Collectively; our results suggest that curcumin and related polyphenolic compounds can be pursued as candidate drug targets for treatment of PD and other neurological diseases.

Cell Adhesion on Amyloid Fibrils Lacking Integrin Recognition Motif

“…␣-Synuclein (␣-Syn) protein was expressed and purified according to the protocol described by Volles and Lansbury (38) in E. coli BL21 (DE3) strain. For ␣-Syn, 30 mg/ml lyophilized protein was dissolved in 20 mM MES buffer, pH 6.0, and low molecular weight ␣-Syn was prepared by passing the dissolved protein through 100 kDa cut-off membrane as described before (39). The Eppendorf tubes containing peptide/protein solutions were placed into an EchoTherm model RT11 rotating mixture (Torrey Pines Scientific) at 50 rpm inside a 37°C incubator.…”

Implantable amyloid hydrogels for promoting stem cell differentiation to neurons

“…In one condition, phosphate buffer was placed on top of the gel surface (condition A) and incubated for up to 21 days. To mimic the possible degradation of the gel in vivo, the gel was mixed with 3.8 μg ml − 1 proteinase K (the enzyme most frequently used for the nonspecific degradation of protein and amyloids 23,24 ) and incubated for 21 days. After 7 and 21 days of incubation, 150 μl of soluble α-Syn was mixed with 3 μl solution of phosphate buffer placed on the top (condition A) to achieve a 2% v/v concentration of degraded gel.…”

“…In one condition, phosphate buffer was placed on top of the gel surface (condition A), and the gel was then incubated up to 21 days. To mimic the degradation of the gel in vivo, the gel was further mixed with 3.8 μg ml − 1 proteinase K, an enzyme most frequently used for the non-specific degradation of proteins and amyloids 23,24 (condition B), and incubated for 21 days. After 7 and 21 days of incubation, 2% v/v degraded gel products from both conditions A and B were added to WT α-Syn, and aggregation was monitored via ThT fluorescence (Figures 3c and d).…”

Curcumin Alters the Salt Bridge-containing Turn Region in Amyloid β(1–42) Aggregates

“…Curcumin, a phenolic compound from the Asian spice turmeric (Curcuma longa), is of great interest for its plausible role in countering neurodegenerative diseases like Parkinson disease (1-3) and Alzheimer disease (AD) 3 (4,5). In vitro studies have shown that curcumin can retard the process of amyloid ␤ (A␤) aggregation (5,6), which is supposed to be the initiator of AD.…”