Dynamic Aspects of Amyloid Fibrils of ñ-Synuclein Related to thePathogenesis of ParkinsonâÂÂs Disease

Abstract

α-synuclein (αSyn) is a 140 amino acid protein of unknown function, abundant in presynaptic terminals of nerve cells. Filamentous aggregates (amyloid fibrils) of αSyn have been shown to be involved with the pathogenesis of Parkinson’s disease, a progressive neurodegenerative disorder. Elucidation of the mechanism of amyloid fibril formation of αSyn is thus important for elucidation of the pathogenesis mechanism of this disease. Amyloid fibril formation is observed for many proteins including, for example, the amyloid-β peptide, the prion protein, and transthyretin. Extensive studies on amyloid fibril formation have characterized structural and kinetic properties of these proteins during fibril formation. Whereas involvement of unfolding/misfolding of the proteins with fibril formation implies that the dynamics of the proteins plays an important role in fibril formation, the dynamic aspects of fibril formation have not been explored very much. In this review, dynamic behavior of αSyn in the monomeric and fibril states is described, based on our recent study on the dynamics of αSyn using quasielastic neutron scattering, by which the dynamics of proteins can be directly measured. It was found that diffusive global motions of the entire molecules and segmental motions within the molecules are observed in the monomeric state but largely suppressed in the fibril state. On the other hand, the amplitudes of the local motions such as side chain motions were found to be larger in the fibril state than in the monomeric state. This implies that significant solvent space exists within the fibrils, which is attributed to αSyn molecule within the fibrils having a distribution of conformations. The larger amplitudes of the side chain motions in the fibril state than in the monomeric state imply that the fibril state is entropically favorable. Implications of this unusual dynamic behavior of αSyn fibrils are discussed in terms of possible clinical relevance.