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
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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 (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)