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Insulin oligomers: what and where are they?
Author(s) -
Belfort Georges,
Sorci Mirco,
Heldt Caryn
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.850.15
Subject(s) - fibrillogenesis , fibril , chemistry , amyloid fibril , biophysics , amyloid (mycology) , ultracentrifuge , circular dichroism , size exclusion chromatography , kinetics , oligomer , amyloid β , biochemistry , biology , medicine , inorganic chemistry , physics , disease , organic chemistry , pathology , quantum mechanics , enzyme
Recent reports have suggested that (i) oligomers, rather than amyloid fibrils, are toxic and possibly cause disease, and (ii) disease progression occurs in the absence of amyloid fibrils. Using a model amyloid protein, the hormone insulin, we have studied the reaction kinetics pathway from folded native hexamers through oligomers to fibrils. Here we report on several experimental methods to detect and follow oligomers during the prefibrillation stage. Small angle x‐ray and neutron scattering, electrospray differential mobility analysis, ultracentrifugation, circular dichroism and size exclusion chromatography were used. Surprisingly, none of these methods detected measurable concentrations of oligomers. This finding suggests that fibrillogenesis may occur without successive transitions through protofibril nuclei or, more probably, with a nuclei‐induced reaction at very low nuclei concentrations. Other experiments have directly (cryo‐electron microscopy) and indirectly (seeding experiment) detected the presence of aggregated structures. The challenge now is to find a separation technique that will selectively isolate the different oligomers and aggregated structures, critical for determining the molecular basis of amyloid‐related diseases. This work was funded by the U.S. Department of Energy, DOE (DE‐FG02‐07ER46429).