Making biological membrane resistant to the toxicity of misfolded protein oligomers: a lesson from trodusquemine

Abstract

Trodusquemine is an aminosterol known to prevent the binding of misfolded protein oligomers to cell membranes and to reduce their toxicity in a wide range of neurodegenerative diseases. Its precise...

Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers

“…The difference of one positive charge between SQ and TRO in its side chain appeared to have a significant impact on the respective efficacies of these aminosterols, with the more charged TRO having an apparently 3-10 times greater protective power relative to an equivalent concentration of SQ. This argument is supported by the observation that TRO decreases the negative charge of the membrane, as determined with zeta-potential measurements, and neutralizes in part the negative moieties of the ganglioside GM1 (Errico et al, 2020), known to mediate oligomer-membrane interaction and oligomer toxicity (Evangelisti et al, 2016). A less positively charged SQ very likely can only be less effective in causing this neutralization.…”

“…In particular, this small molecule was found to localize within the external hydrophilic layer down to the interface between the hydrophilic and hydrophobic layers with a welldefined angle of ca. 55 • for the major axis of the molecule with respect to the normal to the bilayer plane and a superficial positioning of the positively charged spermine moiety (Errico et al, 2020). This causes a decrease in its negative charge, its reinforcement against oligomer penetration, and a redistribution of its cholesterol and ganglioside GM1 molecules, all known to reinforce the membrane against the deleterious action of misfolded protein oligomers (Errico et al, 2020).…”

“…55 • for the major axis of the molecule with respect to the normal to the bilayer plane and a superficial positioning of the positively charged spermine moiety (Errico et al, 2020). This causes a decrease in its negative charge, its reinforcement against oligomer penetration, and a redistribution of its cholesterol and ganglioside GM1 molecules, all known to reinforce the membrane against the deleterious action of misfolded protein oligomers (Errico et al, 2020). The increase in oligomer size observed herein upon SQ addition is expected to reduce oligomer toxicity toward cells, while the increase in oligomer hydrophobicity would be expected to increase the ability of these species to interact with cell membranes and induce dysfunction (Mannini et al, 2014;Cappelli et al, 2016;Limbocker et al, 2020a).…”

“…We refer to this effect as a displacement as SQ was originally shown to displace monomeric and oligomer forms of αS from the membranes of vesicles and cells, respectively (Perni et al, 2017). Moreover, the similar TRO compound was shown to bind to the membrane with high affinity (<500 nM) and make it refractory to the binding of the oligomers (Errico et al, 2020). It is, therefore, likely that aminosterols function by displacing oligomers and by preventing their association with cell membranes prior to oligomer binding.…”

“…In both cases, this molecule could reduce the lifetime or number of oligomeric species by catalyzing their conversion to the fibrillar form for Aβ 42 (Limbocker et al, 2019) or attenuating their rate of formation for αS (Perni et al, 2018). Trodusquemine prevents the toxicity of isolated or stabilized oligomers comprised of the 40-residue form of Aβ (Aβ 40 ), Aβ 42 , αS, and the model protein HypF-N by binding to the cell membrane (Errico et al, 2020), outcompeting oligomers at the cell membrane, and therein displacing these aggregates from cell membranes through a conserved mechanism (Perni et al, 2018;Limbocker et al, 2019Limbocker et al, , 2020b. Trodusquemine was found not to directly target either the size or hydrophobicity of the oligomers at physiological concentrations, but instead to function through a mechanism based on oligomer displacement from the cell membrane in addition to its ability to modulate the kinetics of their assembly (Perni et al, 2018;Limbocker et al, 2019Limbocker et al, , 2020b.…”