Amyloid Fibril Formation of α-Synuclein Is Accelerated by Preformed Amyloid Seeds of Other Proteins

Abstract

␣-Synuclein is one of the causative proteins of familial Parkinson disease, which is characterized by neuronal inclusions named Lewy bodies. Lewy bodies include not only ␣-synuclein but also aggregates of other proteins. This fact raises a question as to whether the formation of ␣-synuclein amyloid fibrils in Lewy bodies may occur via interaction with fibrils derived from different proteins. To probe this hypothesis, we investigated in vitro fibril formation of human ␣-synuclein in the presence of preformed fibril seeds of various different proteins. We used three proteins, Escherichia coli chaperonin GroES, hen lysozyme, and bovine insulin, all of which have been shown to form amyloid fibrils. Very surprisingly, the formation of ␣-synuclein amyloid fibril was accelerated markedly in the presence of preformed seeds of GroES, lysozyme, and insulin fibrils. The structural characteristics of the natively unfolded state of ␣-synuclein may allow binding to various protein particles, which in turn triggers the formation (extension) of ␣-synuclein amyloid fibrils. This finding is very important for understanding the molecular mechanism of Parkinson disease and also provides interesting implications into the mechanism of transmissible conformational diseases.

Application and use of differential scanning calorimetry in studies of thermal fluctuation associated with amyloid fibril formation

“…Once the nucleus is formed, subsequent polymerization proceeds rapidly through the sequential incorporation of precursor molecules into the nucleated fibrils. Many experiments have demonstrated that fibrillation from various proteins involves a lag period that corresponds to the nucleation process before the formation of mature, welldefined amyloid fibrils (Lomakin et al 1996;Naiki et al 1997;Yagi et al 2005;Hamley 2007;Sasahara et al 2008;Xue et al 2008).…”

Oligomerization and Membrane-binding Properties of Covalent Adducts Formed by the Interaction of α-Synuclein with the Toxic Dopamine Metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL)

“…The rate of aS fibrillation can be increased by abolishing the rate-limiting nucleation step through the addition of preformed fibrils (seeds) to the aggregating solution, which act as nuclei for monomer accretion and fibril growth (32). Because DOPAL oxidation products (essentially DOPAL-quinone, referred to here as DPQ) also strongly quench ThT fluorescence, aS fibrillation in the presence of DOPAL cannot be properly evaluated by using ThT (31) unless DOPAL oxidation is inhibited (see below).…”

Dopamine‐induced α‐synuclein oligomers show self‐ and cross‐propagation properties

“…21,22 Given the off-pathway nature of DSOs and their tendency to self-propagate to nonfibrillar aggregates, it is important to understand whether DSOs can cross-propagate nonfibrillar aggregates of Ab. In order to investigate this, monomeric Ab42 (15 mM in 20 mM Tris, 50 mM NaCl, 0.01% NaN 3 at pH 8.0) was incubated with 6.7% (molar percent, 1 lM) DSO at 37 C under quiescent conditions.…”