A causative link between the structure of aberrant protein oligomers and their toxicity

Campioni, Silvia; Mannini, Benedetta; Zampagni, Mariagioia; Pensalfini, Anna; Parrini, Claudia; Evangelisti, Elisa; Relini, Annalisa; Stefani, Massimo; Dobson, Christopher M.; Cecchi, Cristina; Chiti, Fabrizio

doi:10.1038/nchembio.283

Cited by 512 publications

(769 citation statements)

References 46 publications

Supporting

Mentioning

716

Contrasting

Unclassified

Order By: Relevance

“…It is very different from the Aβ 33‐42 fibrils with antiparallel β‐strand conformation. The identified molecular monolayer with high degree of hydrophobic region exposure supports the previous finding27 and also enriches the polymorphic amyloid assemblies. The proposed self‐assembling mechanism of amyloid peptides in the interface might enlighten the mechanistic insight that the secondary conformation of peptides determines the further assembled nanostructures, and this identified molecular structure in amyloid peptide aggregation might possibly be closely related to the pathogenesis of amyloid disease.…”

Section: Discussionsupporting

confidence: 88%

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Liu

Zhang

et al. 2016

Advanced Science

View full text Add to dashboard Cite

The differentiation of protein properties and biological functions arises from the variation in the primary and secondary structure. Specifically, in abnormal assemblies of protein, such as amyloid peptide, the secondary structure is closely correlated with the stable ensemble and the cytotoxicity. In this work, the early Aβ33‐42 aggregates forming the molecular monolayer at hydrophobic interface are investigated. The molecular monolayer of amyloid peptide Aβ33‐42 consisting of novel parallel β‐strand‐like structure is further revealed by means of a quantitative nanomechanical spectroscopy technique with force controlled in pico‐Newton range, combining with molecular dynamic simulation. The identified parallel β‐strand‐like structure of molecular monolayer is distinct from the antiparallel β‐strand structure of Aβ33‐42 amyloid fibril. This finding enriches the molecular structures of amyloid peptide aggregation, which could be closely related to the pathogenesis of amyloid disease.

show abstract

Section: Discussionsupporting

confidence: 88%

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Liu

Zhang

et al. 2016

Advanced Science

View full text Add to dashboard Cite

show abstract

“…The neurotoxic properties of the Aβ peptide must be linked to the propensity of the peptide to form aggregates that possess certain properties in terms of size and biophysical parameters which are required for cell toxicity. It has previously been suggested that the exposure of hydrophobic surfaces is crucial for the toxicity of protein oligomers and of Aβ aggregates promoting interference of the aggregates with membrane structures [14,15]. Our results strongly support these findings and, in addition, show that p-FTAA can be used to probe early formed prefibrillar species that are linked to cell toxicity.…”

Section: In Vivo and In Vitro Toxicity Directly Correlate With Distinsupporting

confidence: 89%

Identification of distinct physiochemical properties of toxic prefibrillar species formed by Aβ peptide variants

Göransson

Nilsson

Kågedal

et al. 2012

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

The formation of amyloid-β peptide (Aβ) aggregates at an early stage during the selfassembly process is an important factor in the development of Alzheimer's disease. The toxic effect is believed to be exerted by prefibrillar species of Aβ. It is therefore important to identify which prefibrillar species are toxic and characterize their distinct properties. In the present study, we investigated the in vitro aggregation behavior of Aβ-derived peptides possessing different levels of neurotoxic activity, using fluorescence spectroscopy in combination with transmission electron microscopy. The toxicity of various Aβ aggregates was assessed by using cultures of human neuroblastoma cells. Through combined use of the fluorescence probe 8-anilino-1-napthalenesulfonate (ANS) and the novel luminescent probe pentamer formyl thiophene acetic acid (p-FTAA), we were able to identify those Aβ peptidederived prefibrillar species which exhibited cellular toxicity. In particular, species, which formed early during the aggregation process and showed strong p-FTAA and ANS fluorescence, were the species that possessed toxic activities. Moreover, by manipulating the aggregation conditions, it was possible to change the capacity of the Aβ peptide to form nontoxic versus toxic species.

show abstract

“…For example, the ability of epsin to induce membrane tubulation and vesiculation is attributed to distortion caused by the insertion of wedgeshaped hydrophobic domains into the membrane (40). The hydrophobicity of the fibril ends may be a property in common with prefibrillar or fibrillar oligomers, which are also reported to damage membranes and are considered as intermediates in amyloid fibril assembly and disassembly (11,(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Direct three-dimensional visualization of membrane disruption by amyloid fibrils

Milanesi

Sheynis

Xue

et al. 2012

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

173

177

View full text Add to dashboard Cite

Protein misfolding and aggregation cause serious degenerative conditions such as Alzheimer's, Parkinson, and prion diseases. Damage to membranes is thought to be one of the mechanisms underlying cellular toxicity of a range of amyloid assemblies. Previous studies have indicated that amyloid fibrils can cause membrane leakage and elicit cellular damage, and these effects are enhanced by fragmentation of the fibrils. Here we report direct 3D visualization of membrane damage by specific interactions of a lipid bilayer with amyloid-like fibrils formed in vitro from β 2 -microglobulin (β 2 m). Using cryoelectron tomography, we demonstrate that fragmented β 2 m amyloid fibrils interact strongly with liposomes and cause distortions to the membranes. The normally spherical liposomes form pointed teardrop-like shapes with the fibril ends seen in proximity to the pointed regions on the membranes. Moreover, the tomograms indicated that the fibrils extract lipid from the membranes at these points of distortion by removal or blebbing of the outer membrane leaflet. Tiny (15-25 nm) vesicles, presumably formed from the extracted lipids, were observed to be decorating the fibrils. The findings highlight a potential role of fibrils, and particularly fibril ends, in amyloid pathology, and report a previously undescribed class of lipid-protein interactions in membrane remodelling.T he failure of molecular chaperones to prevent the accumulation of misfolded proteins results in protein aggregation and amyloid formation, processes associated with severe human degenerative diseases (1, 2). Despite the attention focused on these problems during the century since these disorders were first identified (3-5) and advances in understanding the structure of the cross-β conformation of amyloid fibrils in atomic detail (6, 7), the basic pathological mechanisms of amyloidosis remain poorly understood and therapeutic intervention is lacking. The identity of the toxic species and the mechanisms of cytotoxicity remain major unsolved problems. In some systems, there is evidence suggesting that prefibrillar oligomers, rather than the fully formed fibrils, are the source of toxicity (8, 9). In these cases, cytotoxicity is thought to result from the formation of specific membrane pores (10, 11) although alternative models including membrane destabilization or membrane thinning have also been proposed (12-15). In other cases, toxicity may reside with the amyloid fibrils themselves. Evidence that toxicity correlates with fibrillar assemblies has been reported for yeast and mammalian prion proteins (16, 17), human lysozyme (18), Huntingtin exon 1, α-synuclein (19), and Amyloid-β (Aβ) (20, 21). Furthermore, Aβ plaques have been shown to form rapidly in vivo and to precede neuropathological changes in a mouse model (22). The end surfaces of fibrils (herein termed "fibril ends") are unusually reactive entities: they play a key role in catalyzing recruitment and conformational conversion of amyloid-forming proteins (23, 24) and provide the sites for templated...

show abstract

A causative link between the structure of aberrant protein oligomers and their toxicity

Cited by 512 publications

References 46 publications

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Identification of a Novel Parallel β‐Strand Conformation within Molecular Monolayer of Amyloid Peptide

Identification of distinct physiochemical properties of toxic prefibrillar species formed by Aβ peptide variants

Direct three-dimensional visualization of membrane disruption by amyloid fibrils

Contact Info

Product

Resources

About