1 research outputs found
Lipid Bilayers Significantly Modulate Cross-Fibrillation of Two Distinct Amyloidogenic Peptides
Amyloid plaques comprising misfolded
proteins are the hallmark
of several incurable diseases, including Alzheimer’s disease,
type-II diabetes, Jacob–Creutzfeld disease, and others. While
the exact molecular mechanisms underlying protein misfolding diseases
are still unknown, several theories account for amyloid fiber formation
and their toxic significance. Prominent among those is the “prion
hypothesis” stipulating that misfolded protein seeds act as
“infectious agents” propagating aggregation of nominally
healthy, native proteins. Recent studies, in fact, have reported that
interactions between different amyloid peptides that are partly sequence-related
might also affect fibrillation pathways and pathogenicity. Here, we
present evidence that two structurally and physiologically unrelated
amyloidogenic peptides, the islet amyloid polypeptide (IAPP, the peptide
comprising the amyloid aggregates in type II diabetes) and an amyloidogenic
determinant of the prion protein (PrP), give rise to a significantly
distinct fibrillation pathway when they are incubated together in
the presence of membrane bilayers. In particular, the experimental
data demonstrate that the lipid bilayer environment is instrumental
in initiating and promoting the assembly of morphologically distinct
fibrillar species. Moreover, cross-fibrillation produced peptide species
exhibiting significantly altered membrane interaction profiles, as
compared to the scenario where the two peptides aggregated separately.
Overall, our data demonstrate that membranes constitute a critical
surface-active medium for promoting interactions between disparate
amyloidogenic peptides, modulating both fibrillation pathways as well
as the biophysical properties of the peptide aggregates. This work
hints that membrane-induced cross-fibrillation of unrelated amyloidogenic
peptides might play an insidious role in the molecular pathologies
of protein misfolding diseases