Interaction of Curcumin with α-Synuclein and its Relationship to Curcumin's Ability to Inhibit Fibril Deposit.

Lewy bodies and Lewy neurites in the brain constitute the main histopathological features of Parkinson’s disease (PD), and are comprised of amyloid-like fibrils composed of a small protein named α-synuclein (AS). As the aggregation of AS in the brain has been implicated as a critical step in the development of the diseases, the current search for disease-modifying drugs is focused on molecules that can act on the process of AS deposition in the brain. Recently, curcumin, a constituent of the Indian spice Turmeric, structurally similar to Congo Red, has been demonstrated to bind Aβ amyloid and prevent further oligomerization of Aβ monomers onto growing amyloid β-sheets. Reasoning that oligomerization kinetics and mechanism of amyloid formation may be similar in Parkinson’s disease and Alzheimer’s disease, some authors suggested the use of curcumin to prevent AS aggregation and/or to reduce AS fibrils. Although the mechanisms by which this molecule inhibits Aβ fibril formation and destabilizes preformed fibrils are still unclear, it could be an effective starting template for the development of preventive and therapeutic drugs for PD. With the aim to unravel the mechanism of action of curcumin, we investigated the interactions of curcumin with wild-type AS by NMR, CD and fluorescence spectroscopies. The chiroptical properties of curcumin make this molecule an ideal compound to perform interaction CD studies both in the far-UV and in the visible region of the spectrum. On the other hand, the presence of four tyrosine residues in the AS sequence provide a useful in-site fluorescence probe for quenching studies.