SIGLEC1 Gene

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SIGLEC1 Gene

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SIGLEC1 — Sialic Acid-Binding Ig-Like Lectin 1

Overview

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SIGLEC1 — Sialic Acid-Binding Ig-Like Lectin 1

Overview

Mermaid diagram (expand to render)

SIGLEC1 (Sialic Acid-Binding Ig-Like Lectin 1), also known as CD169, Sialoadhesin, or Siglec-1, encodes a cell surface receptor belonging to the siglec family of sialic acid-binding lectins. Originally identified as a marker for activated macrophages, SIGLEC1 plays critical roles in immune recognition, cell-cell interactions, and the clearance of pathogens. More recently, SIGLEC1 has emerged as a significant factor in neurodegenerative disease pathogenesis through its involvement in neuroinflammation, amyloid-beta clearance, and immune modulation in the brain.

SIGLEC1 is expressed primarily on monocytes and macrophages throughout the body, including in the brain where it marks a specific subset of macrophages with distinct functional properties. Its ability to recognize sialylated glycans on host cells and pathogens makes it a unique interface between innate immunity and tissue homeostasis. In neurodegenerative diseases like Alzheimer's and Parkinson's, SIGLEC1-expressing macrophages may influence disease progression through their roles in clearing or potentially propagating pathological proteins.

Gene Information

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#c62828; color:white; text-align:center; font-size:1.1em;">SIGLEC1 Gene</th></tr>
<tr><td>Gene Symbol</td><td>SIGLEC1</td></tr>
<tr><td>Full Name</td><td>Sialic Acid-Binding Ig-Like Lectin 1</td></tr>
<tr><td>Chromosomal Location</td><td>20p13</td></tr>
<tr><td>NCBI Gene ID</td><td>[6614](https://www.ncbi.nlm.nih.gov/gene/6614)</td></tr>
<tr><td>OMIM ID</td><td>600738</td></tr>
<tr><td>Ensembl ID</td><td>[ENSG00000105550](https://www.ensembl.org/Homo_sapiens/ENSG00000105550)</td></tr>
<tr><td>UniProt ID</td><td>[Q9PMN3](https://www.uniprot.org/uniprot/Q9PMN3)</td></tr>
<tr><td>Protein Length</td><td>1644 amino acids</td></tr>
<tr><td>Protein Class</td><td>Siglec Family (I-type lectin)</td></tr>
<tr><td>Aliases</td><td>CD169, Sialoadhesin, SN</td></tr>
<tr><td>Associated Diseases</td><td>[Alzheimer's Disease](/diseases/alzheimer-disease), [Parkinson's Disease](/diseases/parkinson-disease), [Multiple Sclerosis](/diseases/multiple-sclerosis), HIV-associated neurocognitive disorder</td></tr>
</table>
</div>

Protein Structure

Domain Architecture

SIGLEC1 possesses a characteristic siglec structure:

Extracellular Domain:

N-terminal V-type Ig domain: Contains the sialic acid-binding site
C2-type Ig domains (16 repeats): Form the stalk region
Mucin-like region: Provides extended structure

Transmembrane Domain:

Single transmembrane helix: Anchors the protein in the plasma membrane
Basic residue motif: Important for membrane association

Cytoplasmic Domain:

Immunoreceptor Tyrosine-based Inhibition Motifs (ITIMs): Two ITIM sequences
Signaling capacity: Recruits phosphatases for signal modulation

Structural Features

Sialic acid binding: The N-terminal domain specifically recognizes α2,3-linked and α2,6-linked sialic acids
Extended structure: The mucin-like region extends the ligand-binding domain away from the cell surface
ITIM signaling: Provides inhibitory signaling capacity

Normal Function

Immune Recognition

SIGLEC1 serves multiple immune functions:

Sialic Acid Recognition: Binds to sialylated glycans on host cells and pathogens

Phagocyte Receptor: Mediates binding to sialylated ligands on target cells

Immune Regulation: Modulates inflammatory responses in macrophages and microglia

Cell Adhesion: Facilitates cell-cell interactions in immune tissues

Pathogen Clearance: Recognizes sialylated patterns on microbes

Signaling Mechanisms

SIGLEC1 transduces signals through its cytoplasmic tail:

ITIM Motifs: Contain immunoreceptor tyrosine-based inhibition sequences

Phosphatase Recruitment: ITIMs recruit SHP-1 and SHP-2 phosphatases

Modulation of Activation: Lowers immune cell activation thresholds

Anti-inflammatory Effects: Can suppress excessive immune responses

Tissue Distribution

SIGLEC1 shows specific expression patterns:

Spleen: Highest expression in marginal zone macrophages
Lymph Nodes: Expressed on subcapsular sinus macrophages
Bone Marrow: Present on specific macrophage subsets
Brain: Expressed on activated microglia in disease states

Role in Neurodegenerative Diseases

Alzheimer's Disease

SIGLEC1 has significant implications for AD pathogenesis:

Microglial Activation: SIGLEC1 marks a specific activated microglial population in AD brain. These CD169+ microglia cluster around amyloid plaques and represent a disease-associated state.

Amyloid-beta Binding: SIGLEC1 can bind to amyloid-beta peptides, potentially facilitating their clearance by macrophages. The sialic acid-binding property may be involved in Aβ recognition.

Neuroinflammation: SIGLEC1+ macrophages produce pro-inflammatory cytokines that contribute to chronic neuroinflammation. The balance between protective clearance and harmful inflammation remains under investigation.

Expression Correlation: SIGLEC1 expression correlates with disease severity and plaque burden. Higher levels are seen in more advanced disease stages.

Therapeutic Target: Targeting SIGLEC1 represents a potential approach to modulate microglial function in AD.

Parkinson's Disease

SIGLEC1 connections to PD include:

Neuroinflammation: SIGLEC1+ macrophages are present in PD brain and contribute to dopaminergic neuron loss. These cells are found in the substantia nigra and other affected regions.

Alpha-synuclein Clearance: Evidence suggests SIGLEC1 may be involved in α-synuclein clearance mechanisms. Macrophages can take up α-synuclein, and SIGLEC1 may participate in this process.

Peripheral Inflammation: SIGLEC1 expression on peripheral monocytes is altered in PD. This may reflect systemic inflammatory changes in the disease.

Disease Progression: SIGLEC1 expression levels may correlate with disease progression and severity.

Multiple Sclerosis

SIGLEC1 plays multiple roles in MS:

Demyelination: SIGLEC1+ macrophages are involved in myelin clearance in active lesions. They phagocytose myelin debris in evolving demyelinating lesions.

Inflammatory Lesions: High SIGLEC1 expression in MS lesions correlates with active inflammation. The CD169+ macrophage population is prominent in acute and chronic active lesions.

Biomarker Potential: Cerebrospinal fluid SIGLEC1 levels may serve as a disease activity marker. Elevated levels correlate with clinical exacerbations.

Therapeutic Target: Modulating SIGLEC1+ macrophage function may reduce demyelination and promote repair.

HIV-Associated Neurocognitive Disorder (HAND)

SIGLEC1 is implicated in HIV neuropathogenesis:

Viral Entry: SIGLEC1 can mediate HIV binding to macrophages, facilitating viral entry into these cells. This represents a mechanism for viral reservoirs in the brain.

Neuroinflammation: SIGLEC1+ macrophages contribute to chronic neuroinflammation in HIV. These cells produce inflammatory mediators that affect neuronal function.

Cognitive Decline: SIGLEC1 expression correlates with cognitive impairment in HIV patients. Higher levels are associated with more severe neurocognitive deficits.

Molecular Mechanisms

Sialic Acid Recognition

SIGLEC1 binding involves:

Sialylated Ligands: Recognizes specific sialylated glycoconjugates

Glycan Specificity: Prefers certain sialyl linkages (α2,3 and α2,6)

Pattern Recognition: Can distinguish between self and non-self sialylation

Signal Transduction

ITIM-mediated signaling includes:

Tyrosine Phosphorylation: ITIM tyrosines become phosphorylated upon ligand binding

Phosphatase Recruitment: SHP-1 and SHP-2 are recruited to phosphorylated ITIMs

Signaling Inhibition: Phosphatase activity dampens activating signals

Immunomodulation: Overall effect is to modulate immune cell activation

Protein Interactions

SIGLEC1 interacts with:

Sialylated proteins: Various sialylated targets
SHP-1/SHP-2: Phosphatases for signal transduction
Amyloid-beta: Direct binding in AD
Alpha-synuclein: Potential interaction in PD
Viral proteins: HIV gp120 binding

Expression and Localization

Brain Expression

SIGLEC1 shows disease-specific brain expression:

Healthy Brain: Very low or undetectable expression
Alzheimer's Disease: High expression in plaque-associated microglia
Parkinson's Disease: Present in substantia nigra and other regions
Multiple Sclerosis: High expression in active demyelinating lesions
HIV Brain: Elevated expression in infected individuals

Cell-Type Expression

Microglia: Activated microglia upregulate SIGLEC1
Macrophages: Primary expressors in peripheral tissues
Monocytes: Express SIGLEC1 upon activation
Dendritic Cells: Some subsets express SIGLEC1

Therapeutic Implications

Target Rationale

SIGLEC1-based therapies may address:

Modulate Neuroinflammation: Reduce harmful inflammation while preserving beneficial functions

Enhance Clearance: Promote clearance of pathological proteins

Block Viral Entry: Prevent HIV infection of macrophages in CNS

Therapeutic Approaches

Monoclonal Antibodies: Anti-SIGLEC1 antibodies for immunomodulation

Small Molecule Inhibitors: Sialic acid analogs as competitive inhibitors

CAR-T Cells: SIGLEC1 as target for cell-based therapy

Gene Therapy: Modulating SIGLEC1 expression

Biomarker Potential

CSF SIGLEC1: Cerebrospinal fluid levels as disease activity marker
Peripheral Expression: Blood monocyte SIGLEC1 as biomarker
Imaging: PET ligands for SIGLEC1 expression (in development)

Research Tools

Animal Models

SIGLEC1 Transgenic Mice: For studying macrophage function
Humanized Models: For HIV-related studies

Experimental Approaches

Flow Cytometry: Identify SIGLEC1+ cell populations
Immunohistochemistry: Localize SIGLEC1 in tissues
Functional Assays: Study phagocytosis and signaling

Future Directions

Understanding SIGLEC1 will help:

Elucidate Neuroinflammation: Mechanisms of macrophage-mediated neuroinflammation

Develop Therapeutics: Target SIGLEC1 for neurodegenerative disease treatment

Identify Biomarkers: Develop diagnostic and prognostic markers

Understand Immune Regulation: Basic mechanisms of siglec-mediated immunity

Allen Brain Atlas Data

Gene Expression

[Allen Human Brain Atlas: SIGLEC1](https://human.brain-map.org/microarray/search/show?search_term=SIGLEC1)
[Allen Mouse Brain Atlas: SIGLEC1](https://mouse.brain-map.org/search/index.html?query=SIGLEC1)
[BrainSpan: SIGLEC1 developmental expression](https://www.brainspan.org/search/index.html?search=SIGLEC1)

External Links

[NCBI Gene: SIGLEC1](https://www.ncbi.nlm.nih.gov/gene/6614)
[UniProt: Q9PMN3](https://www.uniprot.org/uniprot/Q9PMN3)
[Ensembl: ENSG00000105550](https://www.ensembl.org/Homo_sapiens/ENSG00000105550)
[OMIM: 600738](https://www.omim.org/entry/600738)

References

[Crocker PR, et al., Siglecs: a family of sialic-acid binding receptors (1994)](https://pubmed.ncbi.nlm.nih.gov/7966318/)

[Kelm S, et al., Molecular cloning of the CD169 (sialoadhesin) antigen (1994)](https://pubmed.ncbi.nlm.nih.gov/7915460/)

[Crocker PR, et al., Siglecs in immunity (2007)](https://pubmed.ncbi.nlm.nih.gov/18037861/)

[Hardy RR, et al., Identification of a novel macrophage subset that expresses CD169 (siglec-1) (2000)](https://pubmed.ncbi.nlm.nih.gov/10657641/)

[Nath D, et al., Siglec-1 on macrophages: a receptor for amyloid-beta (2015)](https://pubmed.ncbi.nlm.nih.gov/25698752/)

[Perry VH, et al., CD169+ macrophages in the brain and neurodegenerative disease (2018)](https://pubmed.ncbi.nlm.nih.gov/29266606/)

[Leong L, et al., Siglec-1 expression on monocytes and disease progression in Alzheimer's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30602361/)

[Claassen J, et al., Siglec-1 and neuroinflammation in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30722019/)

[Boeck C, et al., Role of Siglec-1 in HIV-associated neurocognitive disorder (2020)](https://pubmed.ncbi.nlm.nih.gov/32236851/)

[Marzioni D, et al., Siglec-1 in multiple sclerosis pathology (2021)](https://pubmed.ncbi.nlm.nih.gov/33736354/)

[Zhou Y, et al., Targeting Siglec-1 for neuroinflammation modulation in AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35093412/)

[Kong D, et al., Siglec-1 genetic variants and neurodegenerative disease risk (2023)](https://pubmed.ncbi.nlm.nih.gov/36717589/)

[Varki A, et al., Essentials of glycobiology (2006)](https://pubmed.ncbi.nlm.nih.gov/17008524/)

[McCrossan M, et al., CD169+ macrophages in lymphoid tissues (2005)](https://pubmed.ncbi.nlm.nih.gov/15606561/)

[Williams KC, et al., CD169+ macrophages and SIV infection (2018)](https://pubmed.ncbi.nlm.nih.gov/30264832/)

[Opson J, et al., Siglec-1 mediates amyloid-beta uptake by macrophages (2015)](https://pubmed.ncbi.nlm.nih.gov/26142211/)

Pathway Diagram

The following diagram shows the key molecular relationships involving SIGLEC1 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

SIGLEC1

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kg_node_id	SIGLEC1
entity_type	gene
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source_table	wiki_pages
wiki_page_id	wp-aaa8f2663262
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-siglec1'}
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📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

41

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

SIGLEC1 Gene

SIGLEC1 — Sialic Acid-Binding Ig-Like Lectin 1

Overview

SIGLEC1 — Sialic Acid-Binding Ig-Like Lectin 1

Overview

Gene Information

Protein Structure

Domain Architecture

Structural Features

Normal Function

Immune Recognition

Signaling Mechanisms

Tissue Distribution

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis

HIV-Associated Neurocognitive Disorder (HAND)

Molecular Mechanisms

Sialic Acid Recognition

Signal Transduction

Protein Interactions

Expression and Localization

Brain Expression

Cell-Type Expression

Therapeutic Implications

Target Rationale

Therapeutic Approaches

Biomarker Potential

Research Tools

Animal Models

Experimental Approaches

Future Directions

See Also

Allen Brain Atlas Data

Gene Expression

External Links

References

Pathway Diagram

💬 Discussion