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

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the accumulation of misfolded a-synuclein (aSyn) and myelin disruption. However, the mechanism underlying aSyn accumulation in MSA brains remains unclear. Here, we aimed to identify epsin-2 as a potential regulator of aSyn propagation in MSA brains.In the MSA mouse model, PLP-haSyn mice, and FABP7/aSyn hetero-aggregate-injected mice, we initially discovered that fatty acid-binding protein 7 (FABP7) is related to MSA development and forms hetero-aggregates with aSyn, which exhibit stronger toxicity than aSyn aggregates. Moreover, the injected FABP7/aSyn hetero-aggregates in mice selectively accumulated only in oligodendrocytes and Purkinje neurons, causing cerebellar dysfunction.Furthermore, bioinformatic analyses of whole blood from MSA patients and FABP7 knockdown mice revealed that epsin-2, a protein expressed in both oligodendrocytes and Purkinje cells, could potentially regulate FABP7/aSyn hetero-aggregate propagation via clathrin-dependent endocytosis.Lastly, adeno-associated virus type 5-dependent epsin-2 knockdown mice exhibited decreased levels of aSyn aggregate accumulation in Purkinje neurons and oligodendrocytes, as well as improved myelin levels and Purkinje neuron function in the cerebellum and motor performance. These findings suggest that epsin-2 plays a significant role in aSyn accumulation in MSA, and we propose epsin-2 as a novel therapeutic target for MSA.