The fold of α-synuclein fibrils

Vilar, Marçal; Chou, Hui‐Ting; Lührs, Thorsten; Maji, Samir K.; Riek-Loher, Dominique; Verel, René; Manning, Gerard; Stahlberg, Henning; Riek, Roland

doi:10.1073/pnas.0712179105

Cited by 523 publications

(756 citation statements)

References 52 publications

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“…Indeed, triplication of the αS locus was shown to cause PD and αS progressively accumulates in cytosolic vesicles and the ER during disease (Cooper et al, 2006;Colla et al, 2012). Moreover, the C-terminal tail of Rab8a is less affected by nucleotide and membrane binding and can therefore -independent of other Rab8a interactions -contribute to the interaction with the C-terminal domain of αS, which remains accessible in both the soluble and membrane-bound states and even in αS fibrils (Del Mar et al, 2005;Eliezer et al, 2001;Ulmer et al, 2005;Vilar et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, with increasing amounts of Rab8a roundish clumps were visible on the fibrillar surface, suggesting that Rab8a might bind to αS fibrils. An interaction of Rab8a with the C-terminus of fibrillar αS appears possible, as a variety of investigations have shown that the C-terminus of αS remains disordered and accessible in αS fibrils (Del Mar et al, 2005;Vilar et al, 2008).…”

Section: Rab8a Enhances αS Fibrillizationmentioning

confidence: 99%

“…Intra-and intermolecular contacts can be detected in monomeric, unfolded αS and are implicated in modulating the aggregation propensity (Bertoncini et al, 2005;Dedmon et al, 2005;Outeiro et al, 2008;Wu and Baum, 2010). The negatively charged C-terminus remains disordered in several conformational states such as monomeric, fibrillar and membrane-bound αS (Del Mar et al, 2005;Eliezer et al, 2001;Qin et al, 2007;Ulmer et al, 2005;Vilar et al, 2008). In Lewy õbodies, 90% of αS is estimated to be phosphorylated at S129 in the C-terminus (Fujiwara et al, 2002).…”

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confidence: 99%

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α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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Alpha-synuclein (αS) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying αS toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with αS in rodent brain. NMR spectroscopy reveals that the C-terminus of αS binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/αS interaction, Rab8a enhanced αS aggregation and reduced αS-induced cellular toxicity. In addition, Rab8 -the Drosophila ortholog of Rab8a -ameliorated αS-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the αS-Rab8a interaction, phosphorylation of αS at S129 enhanced binding to Rab8a, increased formation of insoluble αS aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and αS cytotoxicity, and underscores the therapeutic potential of targeting this interaction.

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Section: Discussionmentioning

confidence: 99%

Section: Rab8a Enhances αS Fibrillizationmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Yin¹,

Fonseca²,

Eisbach³

et al. 2014

Neurobiology of Disease

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“…Genetic and pathological evidence suggests that the protein α‐synuclein is central to neurodegeneration in PD 4. Specifically, the transition from an intrinsically disordered α‐synuclein monomer through a series of oligomeric intermediates (with varying structures and size) to a highly structured filament5, 6 is recognised to drive pathogenesis in α‐synucleinopathies. Furthermore, aggregates of α‐synuclein exhibit cell–cell transfer, leading to seeding and recruitment of more protein molecules to form additional aggregates that can generate new seeds in an exponential way,7 leading to the region–region spread of disease.…”

mentioning

confidence: 99%

Optical Structural Analysis of Individual α‐Synuclein Oligomers

et al. 2018

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Small aggregates of misfolded proteins play a key role in neurodegenerative disorders. Such species have proved difficult to study due to the lack of suitable methods capable of resolving these heterogeneous aggregates, which are smaller than the optical diffraction limit. We demonstrate here an all‐optical fluorescence microscopy method to characterise the structure of individual protein aggregates based on the fluorescence anisotropy of dyes such as thioflavin‐T, and show that this technology is capable of studying oligomers in human biofluids such as cerebrospinal fluid. We first investigated in vitro the structural changes in individual oligomers formed during the aggregation of recombinant α‐synuclein. By studying the diffraction‐limited aggregates we directly evaluated their structural conversion and correlated this with the potential of aggregates to disrupt lipid bilayers. We finally characterised the structural features of aggregates present in cerebrospinal fluid of Parkinson's disease patients and age‐matched healthy controls.

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“…14 The aggregated, fibrillar form of aS displays the typical, highly ordered, cross-beta structure of amyloid fibrils, with the ordered fibril core containing residues $30-100. [15][16][17][18] Diverse oligomeric forms of the protein have also been observed, including short, ring-like protofibrils, short chain protofibrils, 19 and other more globular forms with different secondary structure contents. 20 Because some of the PD linked aS mutations accelerate fibril formation (A53T, E46K) [21][22][23][24][25] while others inhibit it (A30P), 19 but all increase oligomer formation, oligomers have been proposed to be the toxic forms of the protein.…”

Section: Introductionmentioning

confidence: 99%

Charge neutralization and collapse of the C‐terminal tail of alpha‐synuclein at low pH

2009

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Alpha-synuclein (aS) is the primary component of Lewy bodies, the pathological hallmark of Parkinson's Disease. Aggregation of aS is thought to proceed from a primarily disordered state with nascent secondary structure through intermediate conformations to oligomeric forms and finally to mature amyloid fibrils. Low pH conditions lead to conformational changes associated with increased aS fibril formation. Here we characterize these structural and dynamic changes using solution state NMR measurements of secondary chemical shifts, relaxation parameters, residual dipolar couplings, and paramagnetic relaxation enhancement. We find that the neutralization of negatively charged side-chains eliminates electrostatic repulsion in the C-terminal tail of aS and leads to a collapse of this region at low pH. Hydrophobic contacts between the compact C-terminal tail and the NAC (non-amyloid-b component) region are maintained and may lead to the formation of a globular domain. Transient long-range contacts between the C-terminus of the protein and regions N-terminal to the NAC region are also preserved. Thus, the release of long-range contacts does not play a role in the increased aggregation of aS at low pH, which we instead attribute to the increased hydrophobicity of the protein.

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The fold of α-synuclein fibrils

Cited by 523 publications

References 52 publications

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

α-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner

Optical Structural Analysis of Individual α‐Synuclein Oligomers

Charge neutralization and collapse of the C‐terminal tail of alpha‐synuclein at low pH

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