Direct assessment of the relevance of the α-syn loss-of-function hypothesis to PD is a challenge. At present, there is no imaging protocol specific for α-syn, although this is an active area of research. To the best of our knowledge, there has been no study of striatal synaptosome preparations comparing PD to controls and there may be significant technical limitations to this approach with postmortem tissue. In addition, since numerous neuronal circuits project to the striatum, it may be difficult to discern what effect is directly attributable to nigrostriatal projections. Studies of α-syn in body fluids as a biomarker for PD may hold clues, but often are difficult to interpret in the context of entry of α-syn into these compartments and the potential presence or impairment of mechanisms operating to maintain homeostasis. However, α-syn is enriched in brain and blood, and from the context of PD as a “whole body” syndrome it can be argued that a systemic change in α-syn that characterizes PD may be detectable in blood as a reflection of a general process that affects brain. Taken together, biomarker studies targeting α-syn present a set of mixed results (Malek et al., 2014 for review), documenting increases, decreases and no differences in PD subjects as compared to controls. Many of these conclusions likely are linked to differences in sample collection, preparation and the assay employed. One recent report takes a different approach to circumvent the complexities of accurately measuring α-syn protein in blood and measured α-syn transcripts. They analyzed blood samples from three large cohorts of PD patients and controls from prior and ongoing clinical trials individually. All three cohorts supported the finding of an approximate 20% reduction in α-syn transcripts even in newly diagnosed PD patients (Locascio et al., 2015). However, this finding could be interpreted as support of loss-of-function, gain-of-function, or be unrelated to processes operating in brain.