Unraveling amyloid formation paths of Parkinson's disease protein α-synuclein triggered by anionic vesicles.

IF 7.2 2区 生物学 Q1 BIOPHYSICS
Juris Kiskis, Istvan Horvath, Pernilla Wittung-Stafshede, Sandra Rocha
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引用次数: 17

Abstract

Amyloid formation of the synaptic brain protein α-synuclein (αS) is related to degeneration of dopaminergic neurons in Parkinson's disease patients. αS is thought to function in vesicle transport and fusion and it binds strongly to negatively charged vesicles in vitro. Here we combined circular dichroism, fluorescence and imaging methods in vitro to characterize the interaction of αS with negatively charged vesicles of DOPS (1,2-dioleoyl-sn-glycero-3-phospho-L-serine, sodium salt) and DOPG (1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol), sodium salt) and the consequences of such interactions on αS amyloid formation. We found that lipid head-group chemistry modulates αS interactions and also affects amyloid fiber formation. During the course of the experiments, we made the unexpected discovery that pre-formed αS oligomers, typically present in a small amount in the αS starting material, acted as templates for linear growth of anomalous amyloid fibers in the presence of vesicles. At the same time, the remaining αS monomers were restricted from vesicle-mediated nucleation of amyloid fibers. Although not a dominant process in bulk experiments, this hidden αS aggregation pathway may be of importance in vivo.

揭示由阴离子囊泡引发的帕金森病蛋白α-突触核蛋白淀粉样蛋白形成途径。
突触脑蛋白α-突触核蛋白(αS)淀粉样蛋白的形成与帕金森病患者多巴胺能神经元的变性有关。αS被认为在囊泡运输和融合中起作用,并在体外与带负电荷的囊泡结合强烈。在此,我们结合圆二色性、荧光和体外成像方法,表征了αS与带负电荷的DOPS(1,2-二油基- n-甘油基-3-磷酸- l-丝氨酸,钠盐)和DOPG(1,2-二油基- n-甘油基-3-磷酸-(1'-乙酰甘油),钠盐)囊泡的相互作用,以及这种相互作用对αS淀粉样蛋白形成的影响。我们发现脂质头基化学调节αS相互作用,也影响淀粉样纤维的形成。在实验过程中,我们意外地发现,在αS起始材料中通常少量存在的预形成αS低聚物,在存在囊泡的情况下,充当了异常淀粉样纤维线性生长的模板。同时,剩余αS单体被限制在淀粉样蛋白纤维的囊泡介导成核中。虽然在大量实验中不是显性过程,但这种隐藏的αS聚集途径在体内可能很重要。
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来源期刊
Quarterly Reviews of Biophysics
Quarterly Reviews of Biophysics 生物-生物物理
CiteScore
12.90
自引率
1.60%
发文量
16
期刊介绍: Quarterly Reviews of Biophysics covers the field of experimental and computational biophysics. Experimental biophysics span across different physics-based measurements such as optical microscopy, super-resolution imaging, electron microscopy, X-ray and neutron diffraction, spectroscopy, calorimetry, thermodynamics and their integrated uses. Computational biophysics includes theory, simulations, bioinformatics and system analysis. These biophysical methodologies are used to discover the structure, function and physiology of biological systems in varying complexities from cells, organelles, membranes, protein-nucleic acid complexes, molecular machines to molecules. The majority of reviews published are invited from authors who have made significant contributions to the field, who give critical, readable and sometimes controversial accounts of recent progress and problems in their specialty. The journal has long-standing, worldwide reputation, demonstrated by its high ranking in the ISI Science Citation Index, as a forum for general and specialized communication between biophysicists working in different areas. Thematic issues are occasionally published.
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