LRP1 is a neuronal receptor for α-synuclein uptake and spread

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alpha-synuclein (α-Syn) aggregation and spread are hallmarks of Parkinson's disease (PD) and Lewy body dementia (LBD).
• While both α-Syn and tau proteins spread between neurons, their roles and associated diseases differ.
• Low-density lipoprotein receptor-related protein 1 (LRP1) is known to regulate tau spread, but its role in α-Syn pathology is unclear.

Purpose of the Study:

• To investigate the role of LRP1 in the uptake and spread of α-Syn protein in neurons.
• To determine if LRP1 mediates the internalization of different α-Syn species (monomers, oligomers, fibrils).
• To examine the involvement of α-Syn lysine residues and N-terminus in LRP1-mediated uptake.

Main Methods:

• Established LRP1 knockout (LRP1-KO) human induced pluripotent stem cell (iPSC)-derived neurons (iPSNs).
• Treated iPSNs with fluorescently labeled α-Syn species and measured uptake via flow cytometry.
• Utilized a neuronal LRP1 conditional knockout (Lrp1-nKO) mouse model to assess α-Syn spread in vivo.

Main Results:

• LRP1-KO iPSNs showed significantly reduced uptake of monomeric and oligomeric α-Syn.
• Uptake of α-Syn pre-formed fibrils (PFFs) was also inhibited, though to a lesser extent.
• Blocking α-Syn lysine residues and the N-terminus impaired LRP1-mediated uptake; Lrp1-nKO mice exhibited reduced α-Syn spread.

Conclusions:

• Identified LRP1 as a key regulator of neuronal α-Syn uptake and a mediator of α-Syn spread in the brain.
• This study elucidates LRP1's role in α-Syn trafficking and pathology.
• Findings offer potential therapeutic insights for synucleinopathies like Parkinson's disease.