Figure 1. Insights from mass spectrometry (MS) on the pathway of protein aggregation.

An ensemble of possible structures exist for any given protein, whereby non-native conformations are prone to associate and form aggregates. Nonfibrillar (amorphous) aggregates result from nonspecific interactions between many different conformations. In contrast, association of soluble species (usually monomers) into β-sheet-rich intermediates gives rise to an aggregation nucleus wherein a growing pool of soluble oligomers triggers polymerization and fibrillization. MS-based approaches can provide important biophysical insight at multiple stages of the aggregation pathway, as highlighted in red text.