Epsin2, a novel target for multiple system atrophy therapy via α-synuclein/FABP7 propagation

Multiple system atrophy (MSA) is a neurodegenerative disease showing accumulation of misfolded -synuclein and myelin disruption. However, the mechanism how -synuclein (-syn) accumulate in MSA brain remains unclear. Here, we identify the protein epsin-2 as a novel target for MSA therapy via controlling -synuclein accumulation. In MSA mouse model, PLP-hSyn transgenic mice and FABP7/-syn hetero-aggregates injected mice, we firstly found that fatty acid-binding protein 7 (FABP7) related to MSA development and formed hetero-aggregates with -syn, which exhibited stronger toxicity than -syn aggregates. Furthermore, injected FABP7/-syn hetero-aggregates in mice selectively accumulated in oligodendrocytes and Purkinje neurons and cause cerebellar dysfunction. By bioinformatic analyses, the protein epsin-2 expresses in both oligodendrocyte and Purkinje cells was found as a potential target to regulate FABP7/-syn hetero-aggregates propagation via clathrin-dependent endocytosis. The AAV5-dependent epsin-2 knock-down mice exhibited decreased levels of aggregates accumulation in Purkinje neurons and oligodendrocytes as well as performed improved myelin levels and Purkinje neurons in cerebellum and motor functions. Thus, we propose epsin-2 as a novel and therapeutic candidate for MSA.