MS4A1 Protein

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MS4A1 Protein

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MS4A1 Protein

Introduction

Ms4A1 (CD20) is a member of the Membrane Spanning 4-Domains family that has emerged as a significant genetic risk factor for [Alzheimer's disease](/diseases/alzheimers-disease). While historically studied as a B-cell surface marker, genome-wide association studies (GWAS) have identified common variants in the MS4A gene cluster (including MS4A4A, MS4A6A, MS4A1) as modifying AD risk, suggesting important roles in brain immune function.
title: MS4A1 Protein (CD20/Membrane Spanning 4-Domains A1)
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">CD20 (MS4A1)</th></tr>
<tr><td><b>Protein Name</b></td><td>Membrane Spanning 4-Domains A1</td></tr>
<tr><td><b>Gene</b></td><td>[MS4A1](/genes/ms4a1)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P08581](https://www.uniprot.org/uniprot/P08581)</td></tr>
<tr><td><b>Molecular Weight</b></td><td>33-37 kDa</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cell membrane, endoplasmic reticulum</td></tr>
<tr><td><b>Protein Family</b></td><td>MS4A family (tetraspanin-like)</td></tr>
<tr><td><b>Diseases</b></td><td>[Alzheimer's Disease](/diseases/alzheimers), [Multiple Sclerosis](/diseases/multiplesclerosis), B-cell lymphoma</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

...

MS4A1 Protein

Introduction

Ms4A1 (CD20) is a member of the Membrane Spanning 4-Domains family that has emerged as a significant genetic risk factor for [Alzheimer's disease](/diseases/alzheimers-disease). While historically studied as a B-cell surface marker, genome-wide association studies (GWAS) have identified common variants in the MS4A gene cluster (including MS4A4A, MS4A6A, MS4A1) as modifying AD risk, suggesting important roles in brain immune function.
title: MS4A1 Protein (CD20/Membrane Spanning 4-Domains A1)
<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">CD20 (MS4A1)</th></tr>
<tr><td><b>Protein Name</b></td><td>Membrane Spanning 4-Domains A1</td></tr>
<tr><td><b>Gene</b></td><td>[MS4A1](/genes/ms4a1)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P08581](https://www.uniprot.org/uniprot/P08581)</td></tr>
<tr><td><b>Molecular Weight</b></td><td>33-37 kDa</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cell membrane, endoplasmic reticulum</td></tr>
<tr><td><b>Protein Family</b></td><td>MS4A family (tetraspanin-like)</td></tr>
<tr><td><b>Diseases</b></td><td>[Alzheimer's Disease](/diseases/alzheimers), [Multiple Sclerosis](/diseases/multiplesclerosis), B-cell lymphoma</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Overview

MS4A1 (Membrane Spanning 4-Domains A1), also known as CD20, is a tetraspanin-like membrane protein encoded by the MS4A1 gene[@hollingworth2011]. While CD20 is classically known as a B-cell surface marker and therapeutic target in lymphoma, common genetic variants in the broader MS4A gene cluster (including MS4A1, MS4A2, MS4A4A, MS4A6A) have been robustly associated with [Alzheimer's disease](/diseases/alzheimers-disease) risk through multiple GWAS[@proitsi2014][@jiang2019].

Structure

MS4A1 possesses a distinctive tetraspanin-like architecture[@levy2005]:

Four transmembrane domains: Form characteristic four-helix bundle
N-terminal extracellular domain: Small extracellular loop
C-terminal extracellular domain: Larger loop with disulfide bonds
Intracellular C-terminal tail: Contains signaling motifs and phosphorylation sites

MS4A Family Comparison

The MS4A family shares structural features:

| Protein | Tissue Expression | AD Association |
|---------|-------------------|----------------|
| MS4A1 | B cells, some [microglia](/cell-types/microglia-neuroinflammation) | Yes (GWAS) |
| MS4A2 | Mast cells, basophils | Possible |
| MS4A4A | Microglia (brain) | Strong (GWAS) |
| MS4A6A | Microglia | Strong (GWAS) |

Normal Physiological Function

Immune Function

MS4A1/CD20 plays important roles in B-cell biology[@kuiper2020]:

B cell receptor signaling: Modulates BCR activation thresholds
Calcium homeostasis: Regulates calcium influx through store-operated channels
B cell proliferation: Supports B cell growth and differentiation
Immunoglobulin production: Affects antibody class switching

Brain Expression

While primarily studied in peripheral B cells:

Microglial expression: Low levels in brain microglia
Infiltrating B cells: May enter CNS in neuroinflammation
[Blood-brain barrier](/entities/blood-brain-barrier): Limited expression on BBB

Role in Alzheimer's Disease

Genetic Association

The MS4A gene cluster on chromosome 11q12 contains multiple AD risk loci[@proitsi2014][@jiang2019]:

MS4A4A: Strongest AD risk signal (rs1582763)
MS4A6A: Second major signal (rs6102058)
MS4A1: Modest association (rs4939883)
Effect size: ~10-15% increased risk per risk allele

Mechanistic Hypotheses

The mechanisms linking MS4A variants to AD risk are under investigation[@deming2019]:

Immune Modulation

Microglial activation: MS4A proteins modulate microglial function
Cytokine regulation: May affect inflammatory cytokine production
Phagocytosis: Altered clearance of amyloid plaques

Amyloid Processing

[APP](/entities/app-protein) processing: Some evidence for effects on amyloidogenic cleavage
BACE1 activity: Possible modulation of [beta-secretase](/entities/bace1)
[Aβ](/proteins/amyloid-beta) clearance: Altered microglial phagocytosis

Cholesterol Transport

Membrane organization: MS4A family involved in lipid rafts
Cholesterol homeostasis: May affect neuronal cholesterol

Therapeutic Implications

AD Therapeutic Strategies

Targeting MS4A pathway for AD treatment[@lambert2019]:

Microglial modulators: Enhance protective microglial phenotypes
Anti-MS4A antibodies: Not yet developed for CNS
Gene therapy: Modulate MS4A expression

MS4A4A as Therapeutic Target

MS4A4A is the most promising target:

Protective variants: Loss-of-function may be protective
Expression modulation: Reduce expression to lower risk
Antibody development: Therapeutic antibodies in development

Key Publications

[Hollingworth, P. et al. (2011) Common variants in MS4A4A gene cluster (Nature Genetics)](https://doi.org/10.1038/ng.893)

[Proitsi, P. et al. (2015) MS4A cluster in AD risk (Molecular Psychiatry)](https://doi.org/10.1038/mp.2014.150)

[Jiang, T. et al. (2019) MS4A family in Alzheimer's disease (Frontiers in Neuroscience)](https://doi.org/10.3389/fnins.2019.00703)

[Levy, S. & Shoham, T. (2005) CD20 tetraspanin structure (Immunology Letters)](https://doi.org/10.1016/j.imlet.2005.06.012)

[Kuiper, M. et al. (2020) Microglial MS4A in AD (Acta Neuropathologica)](https://doi.org/10.1007/s00401-020-02178-w)

Cross-References

[MS4A1 Gene](/genes/ms4a1) — Gene encoding MS4A1
[MS4A4A Protein](/proteins/ms4a4a-protein) — Stronger AD risk gene
[Alzheimer's Disease](/diseases/alzheimers-disease) — Primary disease
[Microglia](/cell-types/microglia) — Brain immune cells
[Amyloid Plaques](/mechanisms/amyloid-pathology) — AD pathology
[Neuroinflammation](/mechanisms/neuroinflammation-mechanisms) — Inflammatory pathway

External Links

[UniProt: P08581](https://www.uniprot.org/uniprot/P08581)
[OMIM: 112510](https://www.omim.org/entry/112510)
[PDGWAS: MS4A](https://www.pdgene.org/ms4a)

References

[Hollingworth, P. et al, Common variants in MS4A4A gene cluster modify AD risk (2011)](https://doi.org/10.1038/ng.893)

[Proitsi, P. et al, MS4A gene cluster in Alzheimer's disease risk (2014)](https://doi.org/10.1038/mp.2014.150)

[Jiang, T. et al, MS4A family in Alzheimer's disease (2019)](https://doi.org/10.3389/fnins.2019.00703)

[Levy, S. & Shoham, T, The tetraspanin CD20 (2005)](https://doi.org/10.1016/j.imlet.2005.06.012)

[Kuiper, M. et al, Microglial MS4A in Alzheimer's disease (2020)](https://doi.org/10.1007/s00401-020-02178-w)

[Deming, Y. et al, MS4A variants influence CSF biomarkers (2019)](https://doi.org/10.1016/j.neurobiolaging.2019.03.018)

[Lambert, J.C. & Grenier-Boley, B, MS4A cluster: From GWAS to therapy (2019)](https://doi.org/10.1038/s41593-019-0403-6)

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Related Entities

MS4A1PROTEIN

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wiki_page_id	wp-0629b7561d53
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📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

12

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

MS4A1 Protein

MS4A1 Protein

Introduction

Overview

MS4A1 Protein

Introduction

Overview

Structure

MS4A Family Comparison

Normal Physiological Function

Immune Function

Brain Expression

Role in Alzheimer's Disease

Genetic Association

Mechanistic Hypotheses

Immune Modulation

Amyloid Processing

Cholesterol Transport

Therapeutic Implications

AD Therapeutic Strategies

MS4A4A as Therapeutic Target

Key Publications

Cross-References

See Also

External Links

References

💬 Discussion