ANS Binding Reveals Common Features of Cytotoxic Amyloid Species

Abstract

Oligomeric assemblies formed from a variety of disease-associated peptides and proteins have been strongly associated with toxicity in many neurodegenerative conditions, such as Alzheimer's disease. The precise nature of the toxic agents, however, remains still to be established. We show that prefibrillar aggregates of E22G (arctic) variant of the Abeta(1-42) peptide bind strongly to 1-anilinonaphthalene 8-sulfonate and that changes in this property correlate significantly with changes in its cytotoxicity. Moreover, we show that this phenomenon is common to other amyloid systems, such as wild-type Abeta(1-42), the I59T variant of human lysozyme and an SH3 domain. These findings are consistent with a model in which the exposure of hydrophobic surfaces as a result of the aggregation of misfolded species is a crucial and common feature of these pathogenic species.

Effect of molecular chaperones on aberrant protein oligomers in vitro: super-versus sub-stoichiometric chaperone concentrations

“…Similar behaviour has been observed for -synuclein (Chen et al 2015). (Oma et al, 2005;Bolognesi et al, 2010;Olzscha et al, 2011;Ladiwala et al, 2012). This has also been observed for HypF-N oligomers (Campioni et al, 2010;Bemporad and Chiti, 2012).…”

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

“…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.…”

The small heat shock protein Hsp27 binds α-synuclein fibrils, preventing elongation and cytotoxicity

“…Importantly, we demonstrate that, by binding to α-syn fibrils, Hsp27 significantly decreases hydrophobicity at the fibril surface. This is noteworthy, given the toxicity of aggregates formed from both pathogenic and nonpathogenic proteins correlates with the level of exposed hydrophobicity at the aggregate surface (63). The observed reduction in the relative hydrophobicity of the Hsp27-bound α-syn fibrils suggests that Hsp27 binds to regions of high hydrophobicity and this may decrease the cytotoxicity of the aggregates.…”