Complement Receptor 1 Is a Potential Extracerebral Factor Promoting α-Synuclein Pathology

The deposition of pathological α-synuclein (α-Syn) in the central nervous system (CNS) is a hallmark of Parkinson’s disease (PD). Notably, pathological α-Syn exists not only in the CNS but also in peripheral organs and body fluids in PD patients. Emerging evidence has shown the transmission of α-Syn pathology from the body to the brain. Nevertheless, the factors that drive the aggregation of peripheral α-Syn remain largely unknown. Here, we revealed that complement receptor 1 (CR1), a component of the peripheral blood system, acts as a promoter of α-Syn pathology. The transmembrane domain of CR1 (CR1-TM) exacerbates α-Syn phosphorylation and aggregation in vitro. Furthermore, intravenous injection of α-Syn fibrils induced the formation of α-Syn pathology in the brain. Co-administration of CR1-TM exacerbated α-Syn pathology induced by intravenous injection of preformed α-Syn fibrils. Our findings suggest that extracerebral factors such as CR1 can drive α-Syn pathology and serve as therapeutic targets for treating synucleinopathies.

The transmembrane domain of CR1 (CR1-TM) interacts with α-Syn and promotes its phosphorylation and aggregation. Tail vein injection of preformed α-Syn fibrils together with CR1-TM accelerates the development of α-Syn pathology in the brain.