Extracellular LCN2 Binding to 24p3R in Astrocytes Impedes α‐Synuclein Endocytosis in Parkinson's Disease

The spread or transmission of pathologic α-synuclein (α-Syn) is emerging as potentially important driver of Parkinson's disease (PD) pathogenesis. Emerging evidence suggests that astrocytes play an important role in uptake/clearance of extracellular α-Syn. However, underlying mechanisms and molecular entities responsible for uptake/clearance of extracellular α-Syn by astrocytes are not known. Here, it is shown that lipocalin-2 (LCN2) is upregulated in astrocytes of MPTP-treated mice by RNA-Seq analysis and positively correlates with pathologic α-Syn level in α-Syn PFF model. Strikingly, deletion of astrocytic LCN2 significantly prevents the pathologic α-Syn accumulation and neurodegeneration. Moreover, 24p3R as a crucial receptor of α-Syn uptake by astrocytes is identified, as well as an important mediator of α-Syn spread in the brain. 24p3R specifically binds to α-Syn and then mediates α-Syn uptake. LCN2 prevents astrocytic uptake of α-Syn by impeding the binding of 24p3R and α-Syn. The identification of LCN2/24p3R as a key regulator of α-Syn by astrocytes provides a new target for the treatment of PD and related α-synucleinopathies.