LRP1 Regulates the Uptake and Propagation of α-Synuclein

Abstract The accumulation and transmission of α-Synuclein (α-Syn) is vital in the pathogenesis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy body and multiple system atrophy. Clinical progression and severity of synucleinopathies are associated with deposition and spread of protein aggregates. α-Syn spreads between cells in a prion-like manner and causes neurotoxicity. However, the cellular mechanisms underlying misfolded α-Syn accumulation and propagation have not been conclusively determined. Low-density lipoprotein receptor-related protein 1 (LRP1), which is considered as a multifunctional endocytic receptor that is abundantly expressed in neurons, is elevated in the neurons of PD patients. In this study, elevated LRP1 levels were found in PC12 cells treated with extracellular added α-Syn pre-formed fibrils (PFFs) as well as PFFs-injected PD mice. Cytoplasmic α-Syn levels were markedly suppressed by LRP1 knockdown in vitro and in vivo. Additionally, LRP1 levels were elevated in cells transfected with full length and N-terminus of α-Syn. Interactions between α-Syn and LRP1 were mediated by lysine residues in the N-terminus of α-Syn. Furthermore, downregulation of LRP1 in mice effectively suppressed the propagation of α-Syn between neurons. These findings indicate that LRP1 regulates the uptake and propagation of α-Syn in the brains and may be a potential target for the treatment of α-Syn aggregation- and propagation-associated diseases.