α-Synuclein in Central Nervous System and from Erythrocytes, Mammalian Cells, and Escherichia coli Exists Predominantly as Disordered Monomer

Fauvet, Bruno; Mbefo, Martial K.; Fares, Mohamed Bilal; Desobry, Carole; Michael, Sarah; Ardah, Mustafa T.; Tsika, Elpida; Coune, Philippe Guillaume; Prudent, Michel; Lion, Niels; Eliezer, David; Moore, Darren J.; Schneider, Bernard L.; Aebischer, Patrick; El‐Agnaf, Omar M. A.; Masliah, Eliezer; Lashuel, Hilal A.

doi:10.1074/jbc.m111.318949

Cited by 496 publications

(501 citation statements)

References 72 publications

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“…As such, it would be highly desirable to obtain more comprehensive information about α-syn oligomers that have been detected in the cerebrospinal fluid and sera of PD patients [13][14][15][16] through the epitope mapping used here. The challenge will remain to isolate oligomers from clinical specimens of PD patients or other biological systems under near-native conditions [57,58] and elucidate how the oligomers produced in vivo compare with those observed here. …”

Section: Discussionmentioning

confidence: 97%

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Illes‐Toth

Ramos

Cappai

et al. 2015

Biochemical Journal

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Misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell-to-cell transmission of α-syn pathology has been linked to soluble amyloid oligomer populations that precede Lewy body formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. In the present study, we characterize, by ESI-ion mobility spectrometry (IMS)-MS, a specific population of α-syn oligomers. These MS-compatible oligomers were compared with oligomers with known seeding and pore-forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain-of-function. Structurally, the MS compatible oligomers populated a range of species from dimers through to hexamers. Lower-order oligomers were structurally diverse and consistent with unstructured assemblies. Higher-order oligomers were shown to be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases.

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Section: Discussionmentioning

confidence: 97%

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Illes‐Toth

Ramos

Cappai

et al. 2015

Biochemical Journal

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“…This has been shown to be true for disordered monomer AS by several different experimental methods, 7,8 including native gel electrophoresis. 9 Moreover, it emphasizes that caution must be used in interpreting molecular size from methods that are dependent upon the shape of the molecules measured.…”

Section: Resultsmentioning

confidence: 99%

N‐terminal acetylation is critical for forming α‐helical oligomer of α‐synuclein

2012

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The aggregation of the protein a-synuclein (AS) is critical to the pathogenesis of Parkinson's disease. Although generally described as an unstructured monomer, recent evidence suggests that the native form of AS may be an a-helical tetramer which resists aggregation. Here, we show that N-terminal acetylation in combination with a mild purification protocol results in an oligomeric form of AS with partial a-helical structure. N-terminal acetylation of AS could have important implications for both the native and pathological structures and functions of AS. Through our demonstration of a recombinant expression system, our results represent an important step toward biochemical and biophysical characterization of this potentially important form of AS.

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“…Confusingly, however, in the same study electron microscopy failed to detect a monodisperse population of α-synuclein tetramers, and high-resolution NMR studies also did not observe a stable tetramer of α-synuclein, but revealed a dynamic multimerization of α-synuclein molecules at very high concentrations (54). Subsequent work, moreover, demonstrated that both recombinant α-synuclein and native cytosolic α-synuclein purified from brain were monomeric and natively unfolded, suggesting that, at least in brain (where α-synuclein is most highly expressed and its pathological role in neurodegeneration is most important), soluble α-synuclein is a natively unfolded monomer (31,32).…”

Section: Negatively Charged Liposomesmentioning

confidence: 99%

“…The labile association of α-synuclein with membranes (23,24) suggests that binding of α-synuclein to synaptic vesicles, and its dissociation from these vesicles, may regulate its physiological function. Membrane-bound α-synuclein assumes an α-helical conformation (25)(26)(27)(28)(29)(30)(31)(32), whereas cytosolic α-synuclein is natively unfolded and monomeric (refs. 25, 26, 31, and 32; however, see refs.…”

mentioning

confidence: 99%

α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

Burré¹,

Sharma²,

Südhof

2014

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

389

437

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Physiologically, α-synuclein chaperones soluble NSF attachment protein receptor (SNARE) complex assembly and may also perform other functions; pathologically, in contrast, α-synuclein misfolds into neurotoxic aggregates that mediate neurodegeneration and propagate between neurons. In neurons, α-synuclein exists in an equilibrium between cytosolic and membrane-bound states. Cytosolic α-synuclein appears to be natively unfolded, whereas membrane-bound α-synuclein adopts an α-helical conformation. Although the majority of studies showed that cytosolic α-synuclein is monomeric, it is unknown whether membrane-bound α-synuclein is also monomeric, and whether chaperoning of SNARE complex assembly by α-synuclein involves its cytosolic or membrane-bound state. Here, we show using chemical cross-linking and fluorescence resonance energy transfer (FRET) that α-synuclein multimerizes into large homomeric complexes upon membrane binding. The FRET experiments indicated that the multimers of membrane-bound α-synuclein exhibit defined intermolecular contacts, suggesting an ordered array. Moreover, we demonstrate that α-synuclein promotes SNARE complex assembly at the presynaptic plasma membrane in its multimeric membrane-bound state, but not in its monomeric cytosolic state. Our data delineate a folding pathway for α-synuclein that ranges from a monomeric, natively unfolded form in cytosol to a physiologically functional, multimeric form upon membrane binding, and show that only the latter but not the former acts as a SNARE complex chaperone at the presynaptic terminal, and may protect against neurodegeneration.Parkinson's disease | synapse | SNARE proteins | membrane fusion α -Synuclein is an abundant presynaptic protein that physiologically acts to promote soluble NSF attachment protein receptor (SNARE) complex assembly in vitro and in vivo (1-3). Point mutations in α-synuclein (A30P, E46K, H50Q, G51D, and A53T) as well as α-synuclein gene duplications and triplications produce early-onset Parkinson's disease (PD) (4-10). Moreover, α-synuclein is a major component of intracellular protein aggregates called Lewy bodies, which are pathological hallmarks of neurodegenerative disorders such as PD, Lewy body dementia, and multiple system atrophy (11-14). Strikingly, neurotoxic α-synuclein aggregates propagate between neurons during neurodegeneration, suggesting that such α-synuclein aggregates are not only intrinsically neurotoxic but also nucleate additional fibrillization (15-18).α-Synuclein is highly concentrated in presynaptic terminals where α-synuclein exists in an equilibrium between a soluble and a membrane-bound state, and is associated with synaptic vesicles (19)(20)(21)(22). The labile association of α-synuclein with membranes (23, 24) suggests that binding of α-synuclein to synaptic vesicles, and its dissociation from these vesicles, may regulate its physiological function. Membrane-bound α-synuclein assumes an α-helical conformation (25-32), whereas cytosolic α-synuclein is natively unfolded and monomeric (refs. 25, 2...

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α-Synuclein in Central Nervous System and from Erythrocytes, Mammalian Cells, and Escherichia coli Exists Predominantly as Disordered Monomer

Cited by 496 publications

References 72 publications

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

Distinct higher-order α-synuclein oligomers induce intracellular aggregation

N‐terminal acetylation is critical for forming α‐helical oligomer of α‐synuclein

α-Synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation

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