MS4A4A Protein
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">MS4A4A Protein</th>
</tr>
<tr>
<td class="label">
Attribute</td>
<td>
Value</td>
</tr>
<tr>
<td class="label">
Protein Name</td>
<td>MS4A4A Protein</td>
</tr>
<tr>
<td class="label">
Gene</td>
<td>[MS4A4A](/proteins/ms4a4a-protein)</td>
</tr>
<tr>
<td class="label">
UniProt ID</td>
<td>[Q9H5Y7](https://www.uniprot.org/uniprot/Q9H5Y7)</td>
</tr>
<tr>
<td class="label">
PDB ID</td>
<td>Predicted (no experimental structure)</td>
</tr>
<tr>
<td class="label">
Molecular Weight</td>
<td>24 kDa</td>
</tr>
<tr>
<td class="label">
Subcellular Localization</td>
<td>Plasma membrane, endoplasmic reticulum</td>
</tr>
<tr>
<td class="label">
Protein Family</td>
<td>Membrane-Spanning 4-Domains A (MS4A) family</td>
</tr>
<tr>
<td class="label">
Tissue Distribution</td>
<td>Myeloid cells, [microglia](/cell-types/microglia-neuroinflammation), B cells, spleen</td>
</tr>
<tr>
<td class="label">
Brain Expression</td>
<td>Primarily microglia, some [neurons](/entities/neurons)</td>
</tr>
<tr>
<td class="label">Evidence</td>
<td>Details</td>
</tr>
<tr>
<td class="label">
GWAS</td>
<td>MS4A4A locus variants modify AD risk (OR ~0.85-1.15)</td>
</tr>
<tr>
<td class="label">
Expression</td>
<td>Upregulated in AD microglia near plaques</td>
</tr>
<tr>
<td class="label">
Function</td>
<td>Modu
...MS4A4A Protein
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">MS4A4A Protein</th>
</tr>
<tr>
<td class="label">
Attribute</td>
<td>
Value</td>
</tr>
<tr>
<td class="label">
Protein Name</td>
<td>MS4A4A Protein</td>
</tr>
<tr>
<td class="label">
Gene</td>
<td>[MS4A4A](/proteins/ms4a4a-protein)</td>
</tr>
<tr>
<td class="label">
UniProt ID</td>
<td>[Q9H5Y7](https://www.uniprot.org/uniprot/Q9H5Y7)</td>
</tr>
<tr>
<td class="label">
PDB ID</td>
<td>Predicted (no experimental structure)</td>
</tr>
<tr>
<td class="label">
Molecular Weight</td>
<td>24 kDa</td>
</tr>
<tr>
<td class="label">
Subcellular Localization</td>
<td>Plasma membrane, endoplasmic reticulum</td>
</tr>
<tr>
<td class="label">
Protein Family</td>
<td>Membrane-Spanning 4-Domains A (MS4A) family</td>
</tr>
<tr>
<td class="label">
Tissue Distribution</td>
<td>Myeloid cells, [microglia](/cell-types/microglia-neuroinflammation), B cells, spleen</td>
</tr>
<tr>
<td class="label">
Brain Expression</td>
<td>Primarily microglia, some [neurons](/entities/neurons)</td>
</tr>
<tr>
<td class="label">Evidence</td>
<td>Details</td>
</tr>
<tr>
<td class="label">
GWAS</td>
<td>MS4A4A locus variants modify AD risk (OR ~0.85-1.15)</td>
</tr>
<tr>
<td class="label">
Expression</td>
<td>Upregulated in AD microglia near plaques</td>
</tr>
<tr>
<td class="label">
Function</td>
<td>Modulates microglial phagocytosis</td>
</tr>
<tr>
<td class="label">
Therapeutic</td>
<td>Target for immunomodulatory therapy</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Strategy</td>
</tr>
<tr>
<td class="label">
Antibodies</td>
<td>Anti-MS4A4A monoclonal antibodies</td>
</tr>
<tr>
<td class="label">
Small molecules</td>
<td>Modulators of MS4A4A function</td>
</tr>
<tr>
<td class="label">
Gene therapy</td>
<td>Modulating MS4A4A expression</td>
</tr>
<tr>
<td class="label">
Biomarker</td>
<td>MS4A4A as disease biomarker</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">Alzheimer's disease</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/tumor" style="color:#ef9a9a">TUMOR</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">13 edges</a></td>
</tr>
</table>
Introduction
Ms4A4A Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
MS4A4A (Membrane-Spanning 4-Domains A4A) is a membrane protein belonging to the membrane-spanning 4-domains A family, which includes at least 15 members in humans. MS4A4A is expressed primarily in immune cells including microglia in the brain, where it plays important roles in immune regulation and cell signaling. The protein is significantly upregulated in Alzheimer's disease brains, particularly in microglia surrounding amyloid plaques. Genetic variants near the MS4A4A locus have been identified as modifiers of AD risk in genome-wide association studies (GWAS), making MS4A4A an important AD risk gene. The protein is predicted to contain four transmembrane domains and may function as a calcium channel or signal modulator. MS4A4A is being actively explored as a therapeutic target for modulating microglial function in Alzheimer's disease and other neurodegenerative conditions.
Structure
Transmembrane Architecture
MS4A4A exhibits the characteristic MS4A family structure:
- Four transmembrane helices: Spanning the lipid bilayer
- Two extracellular loops: N-terminal and between TM2-TM3
- Two intracellular loops: Short loops between TM1-TM2 and TM3-TM4
- N- and C-termini: Both located in the cytoplasm
Structural Predictions
- Topology: Type III membrane protein (both termini intracellular)
- Dimerization: May form homodimers or heterodimers with other MS4A family members
- Post-translational modifications: N-glycosylation sites in extracellular loops
- Calcium binding: EF-hand like motifs predicted in C-terminal domain
Normal Function
Immune Cell Expression
MS4A4A is predominantly expressed in cells of the myeloid lineage:
- Microglia: Brain-resident macrophages, high expression
- Peripheral macrophages: Blood and tissue macrophages
- B cells: Moderate expression in B lymphocyte lineage
- Dendritic cells: Professional antigen-presenting cells
- Spleen: High expression in splenic immune cells
Proposed Functions
Calcium Signaling
- May function as a calcium channel or regulator
- Modulates intracellular calcium levels in immune cells
- Important for microglial activation and cytokine release
Cell Signaling
- Contains potential phosphorylation sites
- May interact with signaling cascades
- Could modulate immune receptor signaling
Membrane Organization
- May cluster in lipid rafts
- Could organize membrane protein complexes
- Potential role in immune synapse formation
Disease Associations
Alzheimer's Disease
MS4A4A has strong genetic and expression links to AD:
Mechanisms:
- Microglial activation: MS4A4A regulates microglial inflammatory responses
- Phagocytosis: Affects clearance of [amyloid-beta](/proteins/amyloid-beta)
- [TREM2](/proteins/trem2-protein) interaction: May work with other microglial AD risk genes
- Cytokine regulation: Modulates production of inflammatory mediators
Multiple Sclerosis
- Demyelination: MS4A4A expression altered in MS lesions
- Autoimmunity: May affect immune cell function
- Therapeutic potential: Target for MS treatment
Other Conditions
- Autoimmune disorders: Altered expression in some autoimmune conditions
- Cancer: Variable expression in different cancer types
- Infection: May modulate immune response to pathogens
Therapeutic Implications
Drug Development
MS4A4A is an emerging therapeutic target:
Microglial Modulation
- Targeting microglial function: Modulating MS4A4A to enhance Aβ clearance
- Anti-inflammatory approaches: Reducing harmful neuroinflammation
- Phagocytosis enhancement: Improving amyloid plaque clearance
- Combination therapy: With [TREM2](/genes/trem2)-targeting approaches
Challenges
- Understanding exact molecular function
- Achieving brain penetration
- Selectivity over other MS4A family members
- Balancing immune modulation
Research Directions
- Determining precise molecular function
- Developing selective modulators
- Understanding MS4A4A-[TREM2](/proteins/trem2) interactions
- Biomarker development
- Clinical translation
Background
The study of Ms4A4A Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
See Also
- MS4A4A Gene
- MS4A Gene Family
- [TREM2](/genes/trem2)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Microglia](/cell-types/microglia)
- [Amyloid Plaques](/mechanisms/amyloid-hypothesis)
- [Neuroinflammation](/mechanisms/neuroinflammation-pathway)
External Links
- [MS4A4A - UniProt Q9H5Y7](https://www.uniprot.org/uniprot/Q9H5Y7)
- [MS4A4A - NCBI Protein](https://www.ncbi.nlm.nih.gov/protein)
- [MS4A4A - GeneCards](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MS4A4A)
- [Allen Brain Atlas - MS4A4A Expression](https://human.brain-map.org/microarray/search/show?search_term=MS4A4A)
References
[Karch CM, et al, MS4A4A modifies Alzheimer disease risk (2022)](https://pubmed.ncbi.nlm.nih.gov/35030345/)
[Proitsi P, et al, MS4A4A is associated with Alzheimer disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35614317/)
[Huang Y, et al, MS4A4A in microglia and Alzheimer disease (2023)](https://pubmed.ncbi.nlm.nih.gov/36650362/)
[apas A, et al, Microglial MS4A4A in neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/37876123/)
[Efthymiou AG, et al, MS4A4A variants and Alzheimer disease risk (2023)](https://pubmed.ncbi.nlm.nih.gov/37192845/)
[Deming Y, et al, The MS4A gene cluster and Alzheimer disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38109178/)