posted on 2023-09-08, 16:33authored byRitu Joshi, Kiryl Zhaliazka, Aidan P. Holman, Dmitry Kurouski
Abrupt aggregation of misfolded proteins is the underlying
molecular
cause of numerous pathologies including diabetes type 2 and injection
amyloidosis. Although the exact cause of this process is unclear,
a growing body of evidence suggests that protein aggregation is linked
to a high protein concentration and the presence of lipid membranes.
Endosomes are cell organelles that often possess high concentrations
of proteins due to their uptake from the extracellular space. However,
the role of endosomes in amyloid pathologies remains unclear. In this
study, we used a set of biophysical methods to determine the role
of bis(monoacylglycero)phosphate (BMP), the major lipid constituent
of late endosomes on the aggregation properties of insulin. We found
that both saturated and unsaturated BMP accelerated protein aggregation.
However, very little if any changes in the secondary structure of
insulin fibrils grown in the presence of BMP were observed. Therefore,
no changes in the toxicity of these aggregates compared to the fibrils
formed in the lipid-free environment were observed. We also found
that the toxicity of insulin oligomers formed in the presence of a
77:23 mol/mol ratio of BMP/PC, which represents the lipid composition
of late endosomes, was slightly higher than the toxicity of insulin
oligomers formed in the lipid-free environment. However, the toxicity
of mature insulin fibrils formed in the presence of BMP/PC mixture
was found to be lower or similar to the toxicity of insulin fibrils
formed in the lipid-free environment. These results suggest that late
endosomes are unlikely to be the source of highly toxic protein aggregates
if amyloid proteins aggregate in them.