MS4A6A (Membrane-Spanning 4-Domains A6A) is a member of the membrane-spanning 4-domains A (MS4A) gene family. This gene encodes a tetraspanin-like membrane protein that is primarily expressed in immune cells, particularly in cells of the myeloid lineage including microglia in the brain. MS4A6A has emerged as a significant genetic risk factor for Alzheimer's disease (AD) through genome-wide association studies (GWAS).
The MS4A6A gene is located on chromosome 11q12.2, within a cluster of MS4A genes (MS4A1-MS4A6). The gene encodes a 246-amino acid protein with: [1]
The MS4A family includes at least 12 genes with similar structure, many of which have roles in immune cell signaling and function. [2]
In the nervous system, MS4A6A is primarily expressed in: [3]
Microglia: The brain's resident immune cells
Myeloid Cells: Including monocytes and macrophages
Limited Neuronal Expression: Low expression in certain neuronal populations
MS4A6A is one of the most significant AD risk genes identified by GWAS: [4]
Given its immune cell expression, MS4A6A variants may influence multiple sclerosis susceptibility:
Emerging evidence suggests MS4A6A may play roles in:
MS4A6A represents a promising therapeutic target:
Expression increases with age in brain tissue.
MS4A6A interacts with:
MS4A6A is a microglial-expressed protein that has emerged as a significant genetic risk factor for Alzheimer's disease. Its role in modulating microglial function and immune responses makes it a compelling therapeutic target for AD and potentially other neurodegenerative diseases characterized by neuroinflammation.
Hollingworth et al. Common variants in MS4A4A modify AD risk (2011). 2011. ↩︎
Vasquez et al. MS4A6A and microglial activation in AD (2013). 2013. ↩︎
Proitsi et al. MS4A gene cluster and AD endophenotypes (2015). 2015. ↩︎
Jiang et al. MS4A6A in neuroinflammation (2022). 2022. ↩︎