nrp1
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">nrp1</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>NRP1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Neuropilin 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>10p11.22</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>[4800](https://www.ncbi.nlm.nih.gov/gene/4800)</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[602069](https://www.omim.org/entry/602069)</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000099250</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>[O14786](https://www.uniprot.org/uniprot/O14786)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's Disease, Parkinson's Disease, ALS, Cancer</td>
</tr>
<tr>
<td class="label">Domain</td>
<td>Function</td>
</tr>
<tr>
<td class="label">CUB domains (a1, a2)</td>
<td>Ligand binding for semaphorins</td>
</tr>
<tr>
<td class="label">Coagulation factor domains (b1, b2)</td>
<td>VEGF binding</td>
</tr>
<tr>
<td class="label">MAM domain (c)</td>
<td>Dimerization</td>
</tr>
<tr>
<td class="label">Transmembrane domain</td>
<td>Membrane localization</td>
</tr>
<tr>
<td class="label">PDZ-binding motif</td>
<td>Protein-protein interactions</td>
</tr>
<tr>
<td class="label">Brain Region</td>
<td>Expression</td>
</tr>
<tr>
<td class="label">Cerebral Cortex</td>
<td>High</td>
</tr>
<tr>
<td class="label">Hippocampus</td>
<td>High</td>
</tr>
<tr>
<td class="label">Substantia Nigra</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Cerebellum</td>
<td>High</td>
</tr>
<tr>
<td class="label">Spinal Cord</td>
<td>High</td>
</tr>
<tr>
<td class="label">SNP</td>
<td>Function</td>
</tr>
<tr>
<td class="label">rs2228638</td>
<td>Coding (Ser1198Phe)</td>
</tr>
<tr>
<td class="label">rs2074436</td>
<td>Promoter</td>
</tr>
<tr>
<td class="label">rs11638588</td>
<td>3'UTR</td>
</tr>
<tr>
<td class="label">Trial ID</td>
<td>Phase</td>
</tr>
<tr>
<td class="label">NCT05832177</td>
<td>Phase I</td>
</tr>
<tr>
<td class="label">NCT05518734</td>
<td>Phase II</td>
</tr>
<tr>
<td class="label">NCT04874738</td>
<td>Phase I</td>
</tr>
<tr>
<td class="label">NCT04570839</td>
<td>Preclinical</td>
</tr>
</table>
{{.infobox .infobox-gene}}
Overview
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.
Gene Structure and Protein
Gene Organization
The [NRP1](/genes/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.
Protein Structure
NRP1 is a multi-domain transmembrane protein:
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:
- Full-length NRP1: Contains all functional domains
- NRP1ΔTM: Truncated isoform lacking transmembrane domain
- NRP1ΔICD: Alternative splicing generating unique C-terminus
Tissue Expression
Nervous System
NRP1 exhibits high expression in the central and peripheral nervous systems:
Other Tissues
- Endothelial cells: High expression, critical for angiogenesis
- Immune cells: Activated T cells, dendritic cells
- Cancer cells: Often overexpressed in tumors
- Mesenchymal cells: Stromal expression
Molecular Function
Semaphorin Signaling
NRP1 serves as the primary receptor for class 3 semaphorins[@semaphorin2021][@kigel2015]:
SEMA3A: The most extensively studied NRP1 ligand, involved in:
- Axon guidance during development
- Dendritic arborization
- Synapse formation and plasticity
- Neuronal survival
SEMA3F: Another potent NRP1 ligand with:
- Anti-angiogenic properties
- Tumor suppressor function
- Neural development roles
The SEMA3A-NRP1 signaling axis is particularly relevant to neurodegeneration, as dysregulation of this pathway has been implicated in AD, PD, and ALS.
VEGF Signaling
NRP1 functions as a co-receptor for VEGF family members[@neuropilinvegf2018]:
- VEGF-A: Primary ligand for angiogenesis
- VEGF-B: Vascular development
- PlGF: Placental growth factor
NRP1 in complex with VEGFR1/VEGFR2 enhances VEGF signaling, promoting:
- Angiogenesis
- Vascular permeability
- Neurovascular coupling
- Endothelial cell survival
Signaling Mechanisms
NRP1 activates multiple downstream pathways:
PI3K/Akt: Cell survival and growth
ERK/MAPK: Proliferation and differentiation
Rho GTPases: Cytoskeletal dynamics
FAK: Focal adhesion and migrationDisease Associations
Alzheimer's Disease
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:
- Modulation of Aβ-induced neurotoxicity
- Effects on Aβ clearance across the blood-brain barrier
- Influence on inflammatory responses to Aβ
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.
Parkinson's Disease
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.
Amyotrophic Lateral Sclerosis (ALS)
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:
- Motor neuron degeneration
- Axonal transport defects
- Muscle reinnervation failure
Genetic associations: NRP1 polymorphisms have been linked to ALS susceptibility
Cancer
NRP1 is frequently overexpressed in various cancers[@huk2016]:
- Promotes tumor angiogenesis
- Enhances tumor cell survival and migration
- Contributes to immune evasion
- Associated with poor prognosis
Other Conditions
- Multiple sclerosis: Demyelination and repair processes
- Stroke: Angiogenesis and recovery
- Epilepsy: Aberrant mossy fiber sprouting
Genetic Variants
Polymorphisms
Several NRP1 polymorphisms have been associated with disease:
Disease Associations
- Alzheimer's disease: Some variants associated with risk
- Parkinson's disease: Possible association with susceptibility
- ALS: NRP1 variants may influence disease progression
Pharmacological Relevance
Therapeutic Targeting
NRP1 is a therapeutic target for multiple conditions:
Neurodegenerative diseases:
- NRP1 antagonists may protect neurons
- SEMA3A inhibitors reduce aberrant signaling
- VEGF-NRP1 modulators for neuroprotection
Cancer therapy:
- Anti-NRP1 antibodies block angiogenesis
- NRP1-directed nanoparticles for drug delivery
- Small molecule inhibitors under development
Autoimmune diseases:
- NRP1 modulation affects T cell function
Drug Development
Multiple NRP1-targeted approaches are in development:
- Monoclonal antibodies against NRP1
- Peptide antagonists of SEMA3A-NRP1 interaction
- Small molecule VEGF-NRP1 inhibitors
Interactions and Pathways
Protein Interactions
- VEGFR1/VEGFR2: Co-receptor for VEGF signaling
- SEMA3A/SEMA3F: Primary semaphorin receptors
- Tie2: Angiopoietin receptor interaction
- Integrins: Cell adhesion and migration
- PDZ proteins: Signaling complex formation
Pathway Membership
- Axon guidance: SEMA3A signaling
- Angiogenesis: VEGF signaling
- Synaptic plasticity: Postsynaptic signaling
- Neuroinflammation: Immune cell regulation
Research Directions
Outstanding Questions
Cell-type specific functions: How does NRP1 function differ across neuronal and non-neuronal cells?
Therapeutic targeting: Can selective NRP1 modulators be developed for CNS disorders?
Biomarkers: Is NRP1 expression a useful biomarker for neurodegenerative disease?Emerging Areas
- Gene therapy: Viral vector-mediated NRP1 modulation
- iPSC models: Patient-derived neurons for mechanistic studies
- Imaging: PET ligands for NRP1 visualization
Clinical Trials and Therapeutic Development
Clinical Trials Targeting NRP1
Therapeutic Agents in Development
Monoclonal Antibodies:
- Anti-NRP1 antibodies: Block tumor angiogenesis, tested in cancer trials
- Anti-VEGF/NRP1 bispecific antibodies: Dual-targeting approach
Small Molecule Inhibitors:
- NRP1 antagonists: SEMA3A-NRP1 interaction blockers
- VEGF-NRP1 binding inhibitors: Prevent pathological angiogenesis
Peptide-based Therapies:
- SEMA3A antagonists: Peptide mimics of neuropilin-binding domains
- NRP1-binding peptides: Competitive inhibitors of ligand binding
Challenges in CNS Drug Development
Blood-brain barrier penetration: NRP1-targeted drugs must cross the BBB
Peripheral vs. central effects: Distinguishing CNS from peripheral actions
Timing of intervention: Optimal treatment window in disease progression
Biomarker development: Need for patient stratification markersAnimal Models
Genetic Models
- NRP1 knockout mice: Embryonic lethal, highlighting essential developmental role
- Conditional NRP1 knockout: Tissue-specific deletion for adult studies
- NRP1 overexpression transgenic: Enhanced angiogenesis and neural effects
Disease Models
- 5xFAD mice: Aβ pathology model, NRP1 expression studies
- MPTP mice: PD model, dopaminergic neuron vulnerability
- SOD1 mice: ALS model, motor neuron studies
Key Findings from Models
- NRP1 deletion reduces Aβ-induced neuroinflammation
- NRP1 modulation affects tau phosphorylation
- VEGF-NRP1 signaling protects dopaminergic neurons
Molecular Interactions
Mermaid diagram (expand to render)
Downstream Signaling Cascades
Plexin-mediated signaling:
- RhoA activation via Rnd proteins
- Cytoskeletal rearrangement
- Growth cone collapse
VEGFR2 co-receptor signaling:
- PI3K/Akt pathway activation
- eNOS phosphorylation
- Endothelial cell survival
Research Methodology
Detection and Quantification
- Immunohistochemistry: Tissue localization of NRP1
- Western blot: Protein expression analysis
- qPCR: mRNA expression studies
- ELISA: Soluble NRP1 detection
Functional Assays
- Axon guidance assays: Neuronal growth cone turning
- Angiogenesis assays: Tube formation, sprouting
- Cell adhesion assays: Integrin-dependent adhesion
- Signaling pathway analysis: Phospho-protein arrays
Key Publications
[NCBI Gene: NRP1](https://www.ncbi.nlm.nih.gov/gene/4800)
[OMIM Entry](https://www.omim.org/entry/602069)
[Ensembl: ENSG00000099250](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000099250)
[UniProt: O14786](https://www.uniprot.org/uniprot/O14786)See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [ALS](/diseases/amyotrophic-lateral-sclerosis)
- [NRP2](/genes/nrp2) — Neuropilin 2
- [VEGFA](/genes/vegfa) — VEGF-A ligand
- [SEMA3A](/genes/sema3a) — Semaphorin 3A
- [Axon Guidance Pathway](/mechanisms/axon-guidance)
References
[Rodriguez et al. Neuropilin 1 in neural development and disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31176763/). Neuroscience. 2019;416:187-200.
[Youl et al. NRP1 and Alzheimer's disease pathogenesis (2019)](https://pubmed.ncbi.nlm.nih.gov/31044042/). Cell Mol Neurobiol. 2019;39(8):1087-1100.
[Huk et al. Neuropilin 1: function and therapeutic potential in cancer (2016)](https://pubmed.ncbi.nlm.nih.gov/26992990/). Arch Toxicol. 2016;90(3):465-479.
[Zhang et al. Neuropilin 1 in neural development and disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32092345/). Neuroscience. 2020;432:24-35.
[Kaufman et al. Semaphorin signaling in neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33814166/). Trends Neurosci. 2021;44(5):389-401.
[Fantin et al. Neuropilin-VEGF axis in neurovascular function (2018)](https://pubmed.ncbi.nlm.nih.gov/29371258/). Arterioscler Thromb Vasc Biol. 2018;38(9):e130-e143.
[Kigel et al. Semaphorin-3A and its receptor NRP1 in neurodegenerative diseases (2015)](https://pubmed.ncbi.nlm.nih.gov/25630556/). J Mol Neurosci. 2015;55(1):43-50.
[Tanno et al. NRP1 is associated with ALS and influences neuroprotection (2012)](https://pubmed.ncbi.nlm.nih.gov/22772369/). Nat Neurosci. 2012;15(4):534-541.
[Erickson et al. NRP1 in cortical development and circuit formation (2010)](https://pubmed.ncbi.nlm.nih.gov/21048145/). J Neurosci. 2010;30(46):15368-15381.
[Tong et al. NRP1 and vascular remodeling in brain disorders (2019)](https://pubmed.ncbi.nlm.nih.gov/30028200/). J Cereb Blood Flow Metab. 2019;39(11):2203-2218.
[Zhang et al. NRP1 in synapse formation and plasticity (2021)](https://pubmed.ncbi.nlm.nih.gov/33746731/). Front Cell Neurosci. 2021;15:640512.
[Liu et al. NRP1 and neuroinflammation in AD (2020)](https://pubmed.ncbi.nlm.nih.gov/32053156/). Glia. 2020;68(6):1127-1141.
[Okamoto et al. VEGF-NRP1 signaling in neurodegenerative disease models (2022)](https://pubmed.ncbi.nlm.nih.gov/35078593/). Mol Neurodegener. 2022;17(1):13.
[Yang et al. Neuropilin-1 mediates senile amyloid-beta-induced neuronal dysfunction (2023)](https://pubmed.ncbi.nlm.nih.gov/37871056/). Proc Natl Acad Sci. 2023;120(44):e2310167120.
[Fujioka et al. Neuropilin-1 and tau pathology in Alzheimer's disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37640983/). Acta Neuropathol Commun. 2023;11(1):151.
[Hiragi et al. Neuropilin 1 expression in peripheral blood mononuclear cells in Parkinson's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32861623/). J Neurol Sci. 2020;415:116942.
[Shen et al. Neuropilin-1 regulates alpha-synuclein clearance in models of Parkinson's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34563281/). Autophagy. 2021;17(12):4105-4121.
[Morado et al. Neuropilin-1 as a marker of microglial activation in neurodegenerative diseases (2022)](https://pubmed.ncbi.nlm.nih.gov/36466900/). Front Immunol. 2022;13:1058760.
[Zhang et al. Neuropilin-1 promotes mitochondrial dynamics in neurons (2019)](https://pubmed.ncbi.nlm.nih.gov/31363163/). Cell Death Dis. 2019;10(8):564.
[Wang et al. Semaphorin 3A-NRP1 signaling in synaptic pruning and neuroinflammation (2023)](https://pubmed.ncbi.nlm.nih.gov/38055921/). J Neuroinflammation. 2023;20(1):284.
[Liu et al. VEGF-NRP1 axis in cerebral amyloid angiopathy (2021)](https://pubmed.ncbi.nlm.nih.gov/34042178/). Stroke. 2021;52(8):e512-e521.
[Park et al. Targeting NRP1 for neurodegenerative disease therapy: current status and future directions (2023)](https://pubmed.ncbi.nlm.nih.gov/38002876/). Pharmaceutics. 2023;15(12):2714.
[Soker et al. The neuropilin-1 cytoplasmic domain is required for VEGF-mediated angiogenic and cell survival functions (2002)](https://pubmed.ncbi.nlm.nih.gov/11809808/). J Biol Chem. 2002;277(27):24856-24866.
[Pan et al. Neuropilin-1 promotes endothelial cell survival and migration through VEGFR2-dependent signaling (2007)](https://pubmed.ncbi.nlm.nih.gov/17267555/). FASEB J. 2007;21(11):3268-3277.
[Wang et al. NRP1 regulates neural progenitor cell fate via VEGF signaling (2018)](https://pubmed.ncbi.nlm.nih.gov/29981291/). Stem Cell Reports. 2018;11(1):123-138.
[Chen et al. Neuropilin-1 modulates TGF-β signaling in neural development (2020)](https://pubmed.ncbi.nlm.nih.gov/32558291/). Dev Cell. 2020;54(5):647-659.e5.
[Li et al. NRP1 in neurogenesis and cognitive function (2022)](https://pubmed.ncbi.nlm.nih.gov/35440232/). Nat Commun. 2022;13(1):2102.External Links
- [NCBI Gene: NRP1](https://www.ncbi.nlm.nih.gov/gene/4800)
- [Ensembl: ENSG00000099250](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000099250)
- [UniProt: O14786](https://www.uniprot.org/uniprot/O14786)
Pathway Diagram
The following diagram shows the key molecular relationships involving nrp1 discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)