Effect of UV Light on Amyloidogenic Proteins: Nucleation and Fibril Extension

Abstract

Amyloid fibril formation is associated with a large number of neurode-generative diseases. Understanding the molecular details of amyloidogenesis is critical for developing strategies to intervene in the pathological process. Formation of amyloid fibrils is a three-stage process: structural perturbation, nucleation and fibril extension. Absorption of UV light is known to perturb protein conformation and lead to aggregation. We have investigated the effect of UV light on three amyloido-genic proteins: prion protein, ß2-microglobulin and α-synuclein, representing three different classes of proteins, largely α-helical, ß-sheet and natively unstructured, respectively. Of these, only prion protein undergoes amorphous aggregation upon UV exposure. Interestingly, all three proteins, after UV exposure, fail to form amyloid fibrils de novo. It is possible that UV exposure compromises nucleation or fibril extension, or both. Interestingly, upon seeding, these UV-exposed proteins formed amyloid fibrils. The fibrils formed by UV-exposed prion protein were morphologically different from those formed by the unexposed protein. Upon UV exposure all the three proteins lose their ability to form de novo fibrils, but remain competent for seeded fibril growth. UV exposure, therefore, selectively compromises the ability of these proteins to nucleate. UV exposure might be of use in investigating the amyloidogenic process, especially the different processes associated with nucleation and fibril extension.