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

Abstract

Background: Multiple system atrophy (MSA) is an adult-onset, fatal neurodegenerative disease featured by propagation of misfolded α-synuclein and dysregulation of myelin integrity in central nervous systems (CNS). In our previous study, we identified that fatty acid binding protein 7 (FABP7), one glial protein regulated α-synuclein (α-syn) toxicity and closely related to oligodendrocyte loss. Here, we investigated how FABP7 works in MSA pathological process. Methods: The mouse model of MSA: PLP-hαSyn transgenic mice (PLP-hαSyn mice) were used for understanding the underling role of FABP7 in α-syn aggregation. In vitro, FABP7/α-syn hetero-aggregates were constructed by recombinant human-α-syn and 6X His-tag human-FABP7. By immunohistochemical analyze of brain tissue from PLP-hαSyn mice and aggregates injection mice, we identified the toxicity of aggregates and the region or cell type in brain which aggregates prefer to propagate. Furthermore, through the bioinformatics analysis of MSA patient blood, PLP mouse brain tissue we found candidate proteins related to α-syn propagation. Then, the hypothesis was verified by adeno-associated virus (AAV) knockdown in aggregates injection mice. Findings: In PLP-hαSyn mice, FABP7 also forms hetero-aggregates with α-syn and the FABP7/α-syn hetero-aggregates exhibited higher molecular weight and stronger toxicity than α-syn aggregates both in vitro and in vivo. The same with PLP-hαSyn mice, in the FABP7/α-syn hetero-aggregates injected mice, aggregates prefer to accumulate in oligodendrocyte and purkinje neurons. By bioinformatics analysis we found the protein epsin-2 as a potential receptor which regulate FABP7/α-syn hetero-aggregates propagate to oligodendrocytes and purkinje neurons. In AAV-dependent epsin-2 knock down mice we observed decreased levels of FABP7/α-syn hetero-aggregates in purkinje neurons and oligodendrocytes. Conclusions: These data suggest that epsin-2 is an important potential therapeutic target for MSA via regulating FABP7/α-syn hetero-aggregates propagation. It is very meaningful for further investigation and developing specific inhibitors. Funding: This work was supported by the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development (JP17dm0107071, JP18dm0107071, JP19dm0107071, and JP20dm0107071).