Perhaps the most direct evidence for an α-syn loss-of-function process related to aggregation comes from the mouse pre-formed fibril (PFF) model of synucleinopathy (Luk et al., 2012). In this model, intracerebral injection of pre-formed fibrils of α-syn seeds misfolding of endogenous α-syn, resulting in progressive accumulation of cytoplasmic aggregates of the protein. In a recent report (Osterberg et al., 2015) the formation of aggregates was tracked over time. The findings indicate that as inclusions mature into a compact form, detection of soluble α-syn shows a parallel decline.