FABP2 is Involved in Intestinal α-Synuclein Pathologies

Background: Recently, the hypothesis that pathological alpha-Synuclein propagates from the gut to the brain has gained attention. Although results from animal studies support this hypothesis, the specific mechanism remains unclear. This study focused on the intestinal fatty acid-binding protein (FABP2), which is one of the subtypes of fatty acid binding proteins localizing in the gut, with the hypothesis that FABP2 is involved in the gut-to-brain propagation of alpha-synuclein. The aim of this study was to clarify the pathological significance of FABP2 in the pathogenesis and progression of synucleinopathy. Methods: We examined the relationship between FABP2 and alpha Synuclein in the uptake of alpha-Synuclein into enteric neurons using primary cultured neurons derived from mouse small intestinal myenteric plexus. We also quantified disease-related protein concentrations in the plasma of patients with synucleinopathy and related diseases, and analyzed the relationship between plasma FABP2 level and progression of the disease. Results: Experiments on alpha-Synuclein uptake in primary cultured enteric neurons showed that following uptake, alpha-Synuclein was concentrated in areas where FABP2 was localized. Moreover, analysis of the plasma protein levels of patients with Parkinson's disease revealed that the plasma FABP2 and alpha-Synuclein levels fluctuate with disease duration. The FABP2/alpha-Synuclein ratio fluctuated more markedly than either FABP2 or alpha-Synuclein alone, depending on the duration of disease, indicating a higher discriminant ability of early Parkinson's disease patients from healthy patients. Conclusions: These results suggest that FABP2 potentially contributes to the pathogenesis and progression of alpha-synucleinopathies. Thus, FABP2 is an important molecule that has the potential to elucidate the consistent mechanisms that lead from the prodromal phase to the onset and subsequent progression of synucleinopathies.