On-Surface Aggregation of 伪-Synuclein at Nanomolar Concentrations Results in Two Distinct Growth Mechanisms
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- 作者：Michael Rabe ; Alice Soragni ; Nicholas P. Reynolds ; Dorinel Verdes ; Ennio Liverani ; Roland Riek ; Stefan Seeger
- 刊名：ACS Chemical Neuroscience
- 出版年：2013
- 出版时间：March 20, 2013
- 年：2013
- 卷：4
- 期：3
- 页码：408-417
- 全文大小：516K
- 年卷期：v.4,no.3(March 20, 2013)
- ISSN：1948-7193
文摘
The aggregation of 伪-synuclein (伪-Syn) is believed to be one of the key steps driving the pathology of Parkinson鈥檚 disease and related neurodegenerative disorders. One of the present hypotheses is that the onset of such pathologies is related to the rise of 伪-Syn levels above a critical concentration at which toxic oligomers or mature fibrils are formed. In the present study, we find that 伪-Syn aggregation in vitro is a spontaneous process arising at bulk concentrations as low as 1 nM and below in the presence of both hydrophilic glass surfaces and cell membrane mimicking supported lipid bilayers (SLBs). Using three-dimensional supercritical angle fluorescence (3D-SAF) microscopy, we observed the process of 伪-Syn aggregation in situ. As soon as 伪-Syn monomers were exposed to the surface, they started to adsorb and aggregate along the surface plane without a prior lag phase. However, at a later stage of the aggregation process, a second type of aggregate was observed. In contrast to the first type, these aggregates showed an extended structure being tethered with one end to the surface and being mobile at the other end, which protruded into the solution. While both types of 伪-Syn aggregates were found to contain amyloid structures, their growing mechanisms turned out to be significantly different. Given the clear evidence that surface-induced 伪-Syn aggregation in vitro can be triggered at bulk concentrations far below physiological concentrations, the concept of a critical concentration initiating aggregation in vivo needs to be reconsidered.