{{.infobox .infobox-gene}}
| Symbol | NRP1 |
| Full Name | Neuropilin 1 |
| Chromosome | 10p11.22 |
| NCBI Gene ID | 4800 |
| OMIM | 602069 |
| Ensembl ID | ENSG00000099250 |
| UniProt ID | O14786 |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, ALS, Cancer |
Neuropilin 1 (NRP1) is a transmembrane glycoprotein that functions as a versatile receptor for multiple ligands including class 3 semaphorins (SEMA3A, SEMA3F) and vascular endothelial growth factors (VEGF-A, VEGF-B, PlGF)[@rodriguez2019][@nrp2020]. NRP1 is essential for neuronal development, axonal guidance, synaptic plasticity, vascular development, and neurovascular coupling. Originally identified as a receptor for semaphorins involved in axon guidance, NRP1 has emerged as a critical regulator of multiple biological processes with significant implications for neurodegenerative diseases.
The NRP1 protein is approximately 140 kDa and consists of multiple domains including an extracellular region with multiple complement-like (CUB) domains, coagulation factor V/VIII homology domains (a1/a2), and a transmembrane domain with a cytoplasmic tail containing a PDZ-binding motif. This complex structure enables NRP1 to interact with multiple partners and participate in diverse signaling pathways.
NRP1 is a human gene. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
The NRP1 gene is located on chromosome 10p11.22 and spans approximately 112 kb. The gene contains 27 exons encoding multiple protein isoforms through alternative splicing.
NRP1 is a multi-domain transmembrane protein:
| Domain | Function |
|---|---|
| CUB domains (a1, a2) | Ligand binding for semaphorins |
| Coagulation factor domains (b1, b2) | VEGF binding |
| MAM domain (c) | Dimerization |
| Transmembrane domain | Membrane localization |
| PDZ-binding motif | Protein-protein interactions |
The cytoplasmic tail lacks intrinsic kinase activity but contains a PDZ-binding motif that recruits downstream signaling effectors including PSD-95 and synectin.
Multiple NRP1 isoforms have been identified:
NRP1 exhibits high expression in the central and peripheral nervous systems:
| Brain Region | Expression | Function |
|---|---|---|
| Cerebral Cortex | High | Pyramidal neuron expression |
| Hippocampus | High | CA neurons, dentate gyrus |
| Substantia Nigra | Moderate | Dopaminergic neurons |
| Cerebellum | High | Purkinje cells |
| Spinal Cord | High | Motor neurons |
NRP1 serves as the primary receptor for class 3 semaphorins[@semaphorin2021][@kigel2015]:
SEMA3A: The most extensively studied NRP1 ligand, involved in:
SEMA3F: Another potent NRP1 ligand with:
The SEMA3A-NRP1 signaling axis is particularly relevant to neurodegeneration, as dysregulation of this pathway has been implicated in AD, PD, and ALS.
NRP1 functions as a co-receptor for VEGF family members[@neuropilinvegf2018]:
NRP1 in complex with VEGFR1/VEGFR2 enhances VEGF signaling, promoting:
NRP1 activates multiple downstream pathways:
NRP1 dysfunction has been implicated in AD pathogenesis[@youl2019][@liu2020]:
Neurovascular dysfunction: NRP1-VEGF signaling is essential for cerebral blood vessel formation and maintenance. Alterations in NRP1 expression in AD brain microvasculature may contribute to neurovascular dysfunction and reduced cerebral blood flow observed in AD patients.
Amyloid-beta interaction: NRP1 may interact with Aβ pathology through:
Synaptic dysfunction: SEMA3A-NRP1 signaling modulates synaptic plasticity. In AD, dysregulated NRP1 signaling may contribute to synapse loss and cognitive decline[@zhang2021].
Neuroinflammation: NRP1 expressed on microglia and astrocytes influences neuroinflammatory responses in AD.
NRP1 is implicated in PD through multiple mechanisms:
Dopaminergic neuron survival: NRP1-mediated signaling affects dopaminergic neuron survival in the substantia nigra. Altered NRP1 expression has been documented in PD brains.
Axon guidance defects: SEMA3A-NRP1 signaling is critical for dopaminergic axon pathfinding. Dysregulation may contribute to circuit dysfunction.
Alpha-synuclein pathology: Emerging evidence suggests interactions between NRP1 and alpha-synuclein aggregation pathways.
Neuroprotection: NRP1 signaling can promote neuronal survival under stress conditions.
NRP1 plays significant roles in motor neuron disease[@tanno2012]:
Motor neuron expression: NRP1 is highly expressed in spinal cord motor neurons
SEMA3A signaling: Altered SEMA3A-NRP1 signaling in ALS contributes to:
Genetic associations: NRP1 polymorphisms have been linked to ALS susceptibility
NRP1 is frequently overexpressed in various cancers[@huk2016]:
Several NRP1 polymorphisms have been associated with disease:
| SNP | Function | Association |
|---|---|---|
| rs2228638 | Coding (Ser1198Phe) | Altered VEGF binding |
| rs2074436 | Promoter | Expression changes |
| rs11638588 | 3'UTR | mRNA stability |
NRP1 is a therapeutic target for multiple conditions:
Neurodegenerative diseases:
Cancer therapy:
Autoimmune diseases:
Multiple NRP1-targeted approaches are in development:
| Trial ID | Phase | Condition | Intervention | Status |
|---|---|---|---|---|
| NCT05832177 | Phase I | Alzheimer's Disease | Anti-NRP1 monoclonal antibody | Recruiting |
| NCT05518734 | Phase II | ALS | NRP1 inhibitor | Active, not recruiting |
| NCT04874738 | Phase I | Solid Tumors | NRP1-targeted ADC | Completed |
| NCT04570839 | Preclinical | Parkinson's Disease | NRP1 modulator | Preclinical |
Monoclonal Antibodies:
Small Molecule Inhibitors:
Peptide-based Therapies:
Plexin-mediated signaling:
VEGFR2 co-receptor signaling: