ArticleMolecular neurodegeneration2022
LRP1 is a neuronal receptor for α-synuclein uptake and spread.
Article in Molecular neurodegeneration, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 101 citations in OpenAlex.
- Article
- High-Throughput Screening Identifies Small-Molecule Inhibitors of the Tau-LRP1 Interaction.bioRxiv : the preprint server for biology · 2026Article
- Luteolin Improves BBB Integrity Following Ischemic Stroke Injury by Downregulating the Expression of LRP1 and MMP9.Phytotherapy research : PTR · 2026Article
- Identification of divergent organ-specific gene and protein expression signatures for mitochondrial function, inflammatory response, and proteostasis in the liver and brain in the rotenone-induced rat model of Parkinson's disease.Molecular biology reports · 2026Article
- Blood-Based α-Synuclein Biomarkers in Parkinson's Disease: Molecular Diversity, Analytical Advances and Clinical Translation.International journal of molecular sciences · 2026Review
- Understanding the genetic imperfections of Lewy body dementia.Molecular neurodegeneration · 2026Review
- The ligand preference of LRP1 is regulated by O-glycans.Science advances · 2026Article
- LRP1 Activation Promotes Metabolic Reprogramming and Mrc1 Expression to Attenuate LPS-Induced Cognitive Deficits: An Integrated Omics Analysis.CNS neuroscience & therapeutics · 2026Article
- Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson's disease.Cell death and differentiation · 2026Article
- Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.Molecular neurodegeneration · 2026Review
- Spatial transcriptomics and single-nucleus RNA sequencing reveal rAAV2- and rAAV9-specific transduction signatures in the mouse liver.Gene therapy · 2026Article
- Single-nucleus brain transcriptomics reveals microglia dysfunction in multiple system atrophy.Nature communications · 2026Article
- circ_0044235 exacerbates neuroinflammation and apoptosis following spinal cord injury by targeting miR-338-5p.Journal of orthopaedic surgery and research · 2026Article
- Human pluripotent stem cell engineering with CRISPR-Cas9 for Parkinson's disease.Experimental & molecular medicine · 2026Review
- Article
- Spatial perturb-seq: single-cell functional genomics within intact tissue architecture.Nature communications · 2026Article
- 3D Visualization and Proteomic Analysis of Human Cardiac Transthyretin Amyloidosis Tissue Reveals Microangiopathy and Capillary Occlusion.bioRxiv : the preprint server for biology · 2026Article
- Nonlinear dynamic genetic regulation identifies peripheral drivers of neurodegenerative disease progression.medRxiv : the preprint server for health sciences · 2026Article
- Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.Frontiers in neuroscience · 2026Review
- Deciphering the Neuroautophagic Interactome: Molecular Circuits Linking Selective Autophagy to Neuropathological Cascades in Neurological Disorders.International journal of biological sciences · 2026Review
15 more citing papers are in PubMed but not listed here.
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19 authors at 4 institutions in 1 country.
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Abstract
backgroundThe aggregation and spread of α-synuclein (α-Syn) protein and related neuronal toxicity are the key pathological features of Parkinson's disease (PD) and Lewy body dementia (LBD). Studies have shown that pathological species of α-Syn and tau can spread in a prion-like manner between neurons, although these two proteins have distinct pathological roles and contribute to different neurodegenerative diseases. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP1) regulates the spread of tau proteins; however, the molecular regulatory mechanisms of α-Syn uptake and spread, and whether it is also regulated by LRP1, remain poorly understood.
methodsWe established LRP1 knockout (LRP1-KO) human induced pluripotent stem cells (iPSCs) isogenic lines using a CRISPR/Cas9 strategy and generated iPSC-derived neurons (iPSNs) to test the role of LRP1 in α-Syn uptake. We treated the iPSNs with fluorescently labeled α-Syn protein and measured the internalization of α-Syn using flow cytometry. Three forms of α-Syn species were tested: monomers, oligomers, and pre-formed fibrils (PFFs). To examine whether the lysine residues of α-Syn are involved in LRP1-mediated uptake, we capped the amines of lysines on α-Syn with sulfo-NHS acetate and then measured the internalization. We also tested whether the N-terminus of α-Syn is critical for LRP1-mediated internalization. Lastly, we investigated the role of Lrp1 in regulating α-Syn spread with a neuronal Lrp1 conditional knockout (Lrp1-nKO) mouse model. We generated adeno-associated viruses (AAVs) that allowed for distinguishing the α-Syn expression versus spread and injected them into the hippocampus of six-month-old Lrp1-nKO mice and the littermate wild type (WT) controls. The spread of α-Syn was evaluated three months after the injection.
resultsWe found that the uptake of both monomeric and oligomeric α-Syn was significantly reduced in iPSNs with LRP1-KO compared with the WT controls. The uptake of α-Syn PFFs was also inhibited in LRP1-KO iPSNs, albeit to a much lesser extent compared to α-Syn monomers and oligomers. The blocking of lysine residues on α-Syn effectively decreased the uptake of α-Syn in iPSNs and the N-terminus of α-Syn was critical for LRP1-mediated α-Syn uptake. Finally, in the Lrp1-nKO mice, the spread of α-Syn was significantly reduced compared with the WT littermates.
conclusionsWe identified LRP1 as a key regulator of α-Syn neuronal uptake, as well as an important mediator of α-Syn spread in the brain. This study provides new knowledge on the physiological and pathological role of LRP1 in α-Syn trafficking and pathology, offering insight for the treatment of synucleinopathies.
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