Competition between crystal and fibril formation in molecular mutations of amyloidogenic peptides

Reynolds, Nicholas P.; Adamčík, Jozef; Berryman, Joshua T.; Handschin, Stephan; Zanjani, Ali Asghar Hakami; Wen, Li; Liu, Kun; Zhang, Afang; Mezzenga, Raffaele

doi:10.1038/s41467-017-01424-4

Cited by 94 publications

(169 citation statements)

References 33 publications

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“…We speculate here that the NACore fibrils observed with cryo-TEM are precipitated fragments of a 3D crystalline peptide phase, and consequently that even the fibrils are meta-stable and not at true thermodynamic equilibrium. This is along similar lines as arguments by Reynolds et al (2017) and Adamcik and Mezzenga (2018).…”

Section: Speculationsupporting

confidence: 86%

Aggregation behavior of the amyloid model peptide NACore

Pallbo

Sparr

Olsson

2019

Quart. Rev. Biophys.

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The aggregation of the 11 residue long NACore peptide segment of α-synuclein (68-GAVVTGVTAVA-78) has been investigated using a combination of cryogenic transmission electron microscopy (cryo-TEM), small- and wide-angle X-ray scattering, and spectroscopy techniques. The aqueous peptide solubility is pH dependent, and aggregation was triggered by a pH quench from pH 11.3 to approximately pH 8 or 6, where the average peptide net charge is weakly negative (pH 8), or essentially zero (pH 6). Cryo-TEM shows the presence of long and stiff fibrillar aggregates at both pH, that are built up from β-sheets, as demonstrated by circular dichroism spectroscopy and thioflavin T fluorescence. The fibrils are crystalline, with a wide angle X-ray diffraction pattern that is consistent with a previously determined crystal structure of NACore. Of particular note is the cryo-TEM observation of small globular shaped aggregates, of the order of a few nanometers in size, adsorbed onto the surface of already formed fibrils at pH 6. The fibrillation kinetics is slow, and occurs on the time scale of days. Similarly slow kinetics is observed at both pH, but slightly slower at pH 6, even though the peptide solubility is here expected to be lower. The observation of the small globular shaped aggregates, together with the associated kinetics, could be highly relevant in relation to mechanisms of secondary nucleation and oligomer formation in amyloid systems.

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Section: Speculationsupporting

confidence: 86%

Aggregation behavior of the amyloid model peptide NACore

Pallbo

Sparr

Olsson

2019

Quart. Rev. Biophys.

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“…The here presented structure therefore hints at the possibility that a different structure 180 or mechanism might be the causative agent for PD, at least for familial PD. This could be a different fibril strain (Peelaerts et al 2015), an oligomeric α-Syn intermediate (Winner et al 2011;Outeiro et al 2008;Danzer et al 2007;Lashuel et al 2002;Villar-Pique et al 2016;Vicente Miranda et al 2017), or the process of aggregation itself (Oueslati, Fournier, and Lashuel 2010;Taschenberger et al 2012;Reynolds et al 2017), with the thermodynamic 185 end-product of aggregation -the amyloid fibril -possibly being involved in the cell-to-cell transmissibility of the disease phenotype (Thakur et al 2017).…”

Section: Resultsmentioning

confidence: 99%

Cryo-EM structure of alpha-synuclein fibrils

Guerrero-Ferreira

Taylor

Mona

et al. 2018

Preprint

143

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Intracellular inclusions of alpha-synuclein are the neuropathological hallmark of progressive disorders called synucleinopathies. Alpha-synuclein fibrils are associated with transmissive cell-to-cell propagation of pathology. We report the structure of an alpha-synuclein fibril (residues 1-121) determined by cryo-electron microscopy at 3.4Å resolution. Two 25 protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50-57, containing three mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft may have implications for fibril elongation, and inform the 30 rational design of molecules for diagnosis and treatment of synucleinopathies.

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“…Despite α-Syn fibrils, other forms of α-Syn might also be involved in neurodegeneration, such as an oligomeric α-Syn intermediate ( Danzer et al, 2007 ; Lashuel et al, 2002 ; Outeiro et al, 2008 ; Vicente Miranda et al, 2017 ; Villar-Piqué et al, 2016 ; Winner et al, 2011 ), or the process of fibril aggregation itself ( Oueslati et al, 2010 ; Reynolds et al, 2017 ; Taschenberger et al, 2012 ). Fibrils of α-Syn show significant fibril strain polymorphism ( Peelaerts et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM structure of alpha-synuclein fibrils

Guerrero-Ferreira

Taylor

Mona

et al. 2018

eLife

481

376

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Parkinson’s disease is a progressive neuropathological disorder that belongs to the class of synucleinopathies, in which the protein alpha-synuclein is found at abnormally high concentrations in affected neurons. Its hallmark are intracellular inclusions called Lewy bodies and Lewy neurites. We here report the structure of cytotoxic alpha-synuclein fibrils (residues 1–121), determined by cryo-electron microscopy at a resolution of 3.4 Å. Two protofilaments form a polar fibril composed of staggered β-strands. The backbone of residues 38 to 95, including the fibril core and the non-amyloid component region, are well resolved in the EM map. Residues 50–57, containing three of the mutation sites associated with familial synucleinopathies, form the interface between the two protofilaments and contribute to fibril stability. A hydrophobic cleft at one end of the fibril may have implications for fibril elongation, and invites for the design of molecules for diagnosis and treatment of synucleinopathies.

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Competition between crystal and fibril formation in molecular mutations of amyloidogenic peptides

Cited by 94 publications

References 33 publications

Aggregation behavior of the amyloid model peptide NACore

Aggregation behavior of the amyloid model peptide NACore

Cryo-EM structure of alpha-synuclein fibrils

Cryo-EM structure of alpha-synuclein fibrils

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