SDS-Induced Fibrillation of α-Synuclein: An Alternative Fibrillation Pathway

Giehm, Lise; Oliveira, Cristiano L. P.; Christiansen, Gunna; Pedersen, Jan Skov; Otzen, Daniel E.

doi:10.1016/j.jmb.2010.05.060

Cited by 189 publications

(232 citation statements)

References 61 publications

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“…We show that αS is likely to aggregate via such an intermediate in the presence of TFE, suggesting that membrane-induced αS aggregation may also involve the formation of a helical intermediate. Furthermore, TFE-induced fibrils are β-sheet rich and resemble previously reported aggregates formed by C terminally truncated αS (11), as well as structures induced by detergent and lipid interactions (12,13), which may be linked to PD initiation and progression (14)(15)(16)(17).…”

supporting

confidence: 80%

“…(12) report images of aggregates induced by incubation of αS in the presence of the polyunsaturated acids arachidonic acid and docosahexaenoic acid which are qualitatively similar to TFE fibrils. Also, while this paper was in review, a study was published which described detergent-induced formation of species that may be similar to our TFE fibrils (13). Although more research must be done to evaluate whether species produced by truncation mutations and/or lipid and detergent interactions are indeed related to TFE fibrils, the potential similarities with previously observed structures are particularly important in light of the hypothesis that intermediate or alternative oligomeric or fibrillar species are responsible for PD toxicity (23), recent findings that C-terminal truncation of αS can lead to neuron loss and increased susceptibility to stress in transgenic mouse models (14,15), and multiple lines of evidence that potentially link lipid interactions and metabolism with PD etiology (16).…”

Section: Discussionmentioning

confidence: 87%

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Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

Anderson

Ramlall

Rospigliosi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

161

171

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Because oligomers and aggregates of the protein α-synuclein (αS) are implicated in the initiation and progression of Parkinson's disease, investigation of various αS aggregation pathways and intermediates aims to clarify the etiology of this common neurodegenerative disorder. Here, we report the formation of short, flexible, β-sheet-rich fibrillar species by incubation of αS in the presence of intermediate (10-20% v∕v) concentrations of 2,2,2-trifluoroethanol (TFE). We find that efficient production of these TFE fibrils is strongly correlated with the TFE-induced formation of a monomeric, partly helical intermediate conformation of αS, which exists in equilibrium with the natively disordered state at low [TFE] and with a highly α-helical conformation at high [TFE]. This partially helical intermediate is on-pathway to the TFE-induced formation of both the highly helical monomeric conformation and the fibrillar species. TFE-induced conformational changes in the monomer protein are similar for wild-type αS and the C-terminal truncation mutant αS1-102, indicating that TFE-induced structural transitions involve the N terminus of the protein. Moreover, the secondary structural transitions of three Parkinson's disease-associated mutants, A30P, A53T, and E46K, are nearly identical to wild-type αS, but oligomerization rates differ substantially among the mutants. Our results add to a growing body of evidence indicating the involvement of helical intermediates in protein aggregation processes. Given that αS is known to populate both highly and partially helical states upon association with membranes, these TFE-induced conformations imply relevant pathways for membrane-induced αS aggregation both in vitro and in vivo.is one of a number of synucleopathies in which aggregation of the protein α-Synuclein (αS) is linked to pathogenesis (1). αS is intrinsically disordered, but in the presence of lipid or detergent vesicles or micelles, adopts a highly helical structure in which its N-terminal region is membrane-bound and the C-terminal tail remains predominantly free and unstructured (2, 3). Although most PD cases are sporadic or idiopathic, three point mutations of α-Synuclein-A53T, A30P, and E46K-are associated with familial and early-onset disease (see Review (4)).In addition to its free and membrane-bound states, αS adopts partially structured intermediate conformations under low-pH or high-temperature conditions (5). A folding intermediate has also been detected at low [TFE] (6). Conditions favoring the formation of these intermediates also promote amyloid fibril growth, possibly implicating intermediate conformers as key species in the aggregation pathways.Here, we examine TFE-induced monomer conformational changes, oligomerization, and fibrillization in detail for wild-type (WT) αS, C terminally truncated WT αS (αS102), and the PDassociated αS mutants A30P, A53T, and E46K, expanding upon previous studies by Munishkina, et. al. (6) and Li, et. al. (7). This research also complements our previous fluorescence correlatio...

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supporting

confidence: 80%

Section: Discussionmentioning

confidence: 87%

Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

Anderson

Ramlall

Rospigliosi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

161

171

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“…11b,c). It is known that globular proteins have the tendency to unfold when combined with ionic surfactants 30,31 . To test this hypothesis, a 0.008 mM ELP5 solution was combined with the oppositely charged commercial surfactant dodecyltrimethylammonium bromide (DTAB) above its critical micelle concentration (18 mM).…”

Section: Resultsmentioning

confidence: 99%

Co-assembly, spatiotemporal control and morphogenesis of a hybrid protein–peptide system

et al. 2015

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ature uses self-assembly to create a widespread variety of complex structures with elaborate geometries and outstanding properties 1 such as hierarchical order, adaptability, selfhealing and bioactivity. Developing new bioinspired processes based on dynamic self-assembly could facilitate the fabrication of synthetic three-dimensional (3D) materials with enhanced complexity, dynamic properties and functionality 2 . Proteins are particularly attractive building blocks because of their versatility and biofunctionality 3 . Elastin-like polypeptides (ELPs) 4 are recombinant proteins that have generated great interest 5 as a result of their modular structure, bioactivity, ease of design and production, and the possibility to create robust and elastic materials 5,6 . ELPs allow for a tunable molecular design 7 and are based on the tropoelastin recurrent motif Val-Pro-Gly-X-Gly (VPGXG), in which X is any amino acid other than proline 7 . This repeating pentapeptide provides ELPs with a thermoresponsive behaviour. Below a critical transition temperature (T t ), the ELP molecule undergoes a reversible-phase transition wherein the protein is soluble in aqueous solution and becomes highly solvated, surrounded by clatharate-like water structures. Above the T t , the hydrophobic domains dehydrate and the protein chain hydrophobically collapses and aggregates to form a phaseseparated state 8 .The use of natural and synthetic proteins to create functional materials has been hindered by the difficulty in controlling their conformation and nanoscale assembly with the precision required to form macroscopic materials. This limitation has driven the development of simpler and more-predictable peptide-based materials 9,10 . Peptide amphiphiles (PAs), for example, are synthetic molecules that can self-assemble into nanofibres and create functional 3D hydrogels that emulate the fibrous architecture of the extracellular matrix (ECM) 11,12 . Nonetheless, most peptide and/or protein materials are formed through equilibrium-based self-assembly approaches that are capable of generating stable supramolecular structures, but with limited hierarchy and spatiotemporal control, which has hindered their functionality 2 .Novel approaches based on the dynamic self-assembly of inorganic building blocks [13][14][15] , actin self-organization 16 and the combination of top-down processes with peptide self-assembly have been reported recently 17 . In particular, Stupp and co-workers have described a self-assembling membrane system obtained through strong electrostatic interactions between PAs and oppositely charged polysaccharides 18 . However, the possibility to exploit the unique structural and functional properties of proteins to create dynamic hierarchical materials remains an elusive target. In this study, we attempt to overcome this hurdle by using self-assembling peptides to promote protein conformational changes and guide their assembly into complex, yet functional, materials. We report the discovery and development of a protein/peptide system t...

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“…7,13,14,50 In addition, aggregation mechanisms for amyloidogenic proteins at interfaces in agreement with our observations are comprehensively described in the literature. 61,62 For instance, Zhu et al reported two distinct onsurface aggregation mechanisms for the amyloidogenic protein SMA predominantly differing in their growth rates. 62 Recently, Giehm et al have observed a continuous accretion during the formation of α-Syn aggregates on SDS micelles rather than a rate-limiting accumulation of a distinct nucleus, 61 which is comparable with the observed growth of the type 1 aggregate in our study.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…61,62 For instance, Zhu et al reported two distinct onsurface aggregation mechanisms for the amyloidogenic protein SMA predominantly differing in their growth rates. 62 Recently, Giehm et al have observed a continuous accretion during the formation of α-Syn aggregates on SDS micelles rather than a rate-limiting accumulation of a distinct nucleus, 61 which is comparable with the observed growth of the type 1 aggregate in our study. In addition to those studies, however, we show here that α-Syn molecules can aggregate on surfaces at bulk concentrations of 1 nM and below, while amyloid fibril formation by α-Syn has been observed in solution only at higher micromolar concentrations.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

On-Surface Aggregation of α-Synuclein at Nanomolar Concentrations Results in Two Distinct Growth Mechanisms

Rabe

Soragni

Reynolds

et al. 2013

ACS Chem. Neurosci.

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The aggregation of α-synuclein (α-Syn) is believed to be one of the key steps driving the pathology of Parkinson's disease and related neurodegenerative disorders. One of the present hypotheses is that the onset of such pathologies is related to the rise of α-Syn levels above a critical concentration at which toxic oligomers or mature fibrils are formed. In the present study, we find that α-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 α-Syn aggregation in situ. As soon as α-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 α-Syn aggregates were found to contain amyloid structures, their growing mechanisms turned out to be significantly different. Given the clear evidence that surface-induced α-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.

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SDS-Induced Fibrillation of α-Synuclein: An Alternative Fibrillation Pathway

Cited by 189 publications

References 61 publications

Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation

Co-assembly, spatiotemporal control and morphogenesis of a hybrid protein–peptide system

On-Surface Aggregation of α-Synuclein at Nanomolar Concentrations Results in Two Distinct Growth Mechanisms

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