nrp1

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nrp1

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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</t

...

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>

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.

Isoforms

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 migration

Disease 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 markers

Animal 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

Receptor Complex Formation

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)

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)

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Related Entities

NRP1

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slug	genes-nrp1
kg_node_id	NRP1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-c6348628ee44
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-nrp1'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

15%

Debates

0

Incoming

3

Outgoing

27

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

nrp1

nrp1

nrp1

Overview

Gene Structure and Protein

Gene Organization

Protein Structure

Isoforms

Tissue Expression

Nervous System

Other Tissues

Molecular Function

Semaphorin Signaling

VEGF Signaling

Signaling Mechanisms

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Cancer

Other Conditions

Genetic Variants

Polymorphisms

Disease Associations

Pharmacological Relevance

Therapeutic Targeting

Drug Development

Interactions and Pathways

Protein Interactions

Pathway Membership

Research Directions

Outstanding Questions

Emerging Areas

Clinical Trials and Therapeutic Development

Clinical Trials Targeting NRP1

Therapeutic Agents in Development

Challenges in CNS Drug Development

Animal Models

Genetic Models

Disease Models

Key Findings from Models

Molecular Interactions

Receptor Complex Formation

Downstream Signaling Cascades

Research Methodology

Detection and Quantification

Functional Assays

Key Publications

See Also

References

External Links

Pathway Diagram

💬 Discussion