The aberrant aggregation of proteins is a key molecular event in the development and progression of a wide range of neurodegenerative disorders. We have shown previously that squalamine and trodusquemine, two natural products in the aminosterol class, can modulate the aggregation of the amyloid-β peptide (Aβ) and of α-synuclein (αS), which are associated with Alzheimer’s and Parkinson’s diseases. In this work, we expand our previous analyses to two squalamine derivatives, des-squalamine and α-squalamine, obtaining further insights into the mechanism by which aminosterols modulate Aβ and αS aggregation. We then characterize the ability of these small molecules to alter the physicochemical properties of stabilized oligomeric species in vitro and to suppress the toxicity of these aggregates to varying degrees toward human neuroblastoma cells. We found that, despite the fact that these aminosterols exert opposing effects on Aβ and αS aggregation under the conditions that we tested, the modifications that they induced to the toxicity of oligomers were similar. Our results indicate that the suppression of toxicity is mediated by the displacement of toxic oligomeric species from cellular membranes by the aminosterols. This study, thus, provides evidence that aminosterols could be rationally optimized in drug discovery programs to target oligomer toxicity in Alzheimer’s and Parkinson’s diseases.
The molecular composition
of the plasma membrane plays a key role
in mediating the susceptibility of cells to perturbations induced
by toxic molecules. The pharmacological regulation of the properties
of the cell membrane has therefore the potential to enhance cellular
resilience to a wide variety of chemical and biological compounds.
In this study, we investigate the ability of claramine, a blood–brain
barrier permeable small molecule in the aminosterol class, to neutralize
the toxicity of acute biological threat agents, including melittin
from honeybee venom and α-hemolysin from
Staphylococcus
aureus
. Our results show that claramine neutralizes
the toxicity of these pore-forming agents by preventing their interactions
with cell membranes without perturbing their structures in a detectable
manner. We thus demonstrate that the exogenous administration of an
aminosterol can tune the properties of lipid membranes and protect
cells from diverse biotoxins, including not just misfolded protein
oligomers as previously shown but also biological protein-based toxins.
Our results indicate that the investigation of regulators of the physicochemical
properties of cell membranes offers novel opportunities to develop
countermeasures against an extensive set of cytotoxic effects associated
with cell membrane disruption.
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