伪-Synuclein Misfolding Assessed with Single Molecule AFM Force Spectroscopy: Effect of Pathogenic Mutations

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• 作者：Alexey V. Krasnoslobodtsev ; Ivan L. Volkov ; Josephat M. Asiago ; Jagadish Hindupur ; Jean-Christophe Rochet ; Yuri L. Lyubchenko
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：October 22, 2013
• 年：2013
• 卷：52
• 期：42
• 页码：7377-7386
• 全文大小：427K
• 年卷期：v.52,no.42(October 22, 2013)
• ISSN：1520-4995

文摘

Misfolding and subsequent aggregation of alpha-synuclein (伪-Syn) protein are critically involved in the development of several neurodegenerative diseases, including Parkinson鈥檚 disease (PD). Three familial single point mutations, A30P, E46K, and A53T, correlate with early onset PD; however, the molecular mechanism of the effects of these mutations on the structural properties of 伪-Syn and its propensity to misfold remains unclear. Here, we address this issue utilizing a single molecule AFM force spectroscopy approach in which structural details of dimers formed by all four variants of 伪-Syn are characterized. Analysis of the force spectroscopy data reflecting contour length distribution for 伪-Syn dimer dissociation suggests that multiple segments are involved in the assembly of the dimer. The interactions are not limited to the central nonamyloid-beta component (NAC) of the protein but rather expand beyond this segment. All three mutations alter the protein鈥檚 folding and interaction patterns affecting interactions far beyond their immediate locations. Implementation of these findings to our understanding of 伪-Syn aggregation pathways is discussed.