ST6GALNAC5 Gene
Overview
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ST6GALNAC5 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ST6GALNAC5</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 5</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1p31.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>256297</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000160584</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9H0X9</td>
</tr>
<tr>
<td class="label">Protein Type</td>
<td>Sialyltransferase</td>
</tr>
<tr>
<td class="label">Primary Expression</td>
<td>Astrocytes, brain</td>
</tr>
<tr>
<td class="label">Function</td>
<td>Sialylation of glycoproteins, neural cell adhesion</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Rationale</td>
</tr>
<tr>
<td class="label">ST6GALNAC5 knockdown</td>
<td>Improves spatial memory in AD mice</td>
</tr>
<tr>
<td class="label">Small molecule inhibitors</td>
<td>Reduce enzyme activity</td>
</tr>
<tr>
<td class="label">CRISPR gene therapy</td>
<td>Precise targeting</td>
</tr>
<tr>
<td class="label">ASO oligonucleotides</td>
<td>Splice modulation</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>
Gene Function
...ST6GALNAC5 Gene
Overview
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ST6GALNAC5 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ST6GALNAC5</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>ST6 N-acetylgalactosaminide alpha-2,6-sialyltransferase 5</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1p31.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>256297</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000160584</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9H0X9</td>
</tr>
<tr>
<td class="label">Protein Type</td>
<td>Sialyltransferase</td>
</tr>
<tr>
<td class="label">Primary Expression</td>
<td>Astrocytes, brain</td>
</tr>
<tr>
<td class="label">Function</td>
<td>Sialylation of glycoproteins, neural cell adhesion</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Rationale</td>
</tr>
<tr>
<td class="label">ST6GALNAC5 knockdown</td>
<td>Improves spatial memory in AD mice</td>
</tr>
<tr>
<td class="label">Small molecule inhibitors</td>
<td>Reduce enzyme activity</td>
</tr>
<tr>
<td class="label">CRISPR gene therapy</td>
<td>Precise targeting</td>
</tr>
<tr>
<td class="label">ASO oligonucleotides</td>
<td>Splice modulation</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">2 edges</a></td>
</tr>
</table>
Gene Function
ST6GALNAC5 encodes a sialyltransferase that catalyzes the addition of sialic acid residues to glycoproteins through an alpha-2,6 linkage. This enzyme is primarily expressed in astrocytes in the brain and plays crucial roles in modulating neural cell surface properties, synaptic function, and cell-cell adhesion[@tsai2020].
Catalytic Activity
The enzyme catalyzes the transfer of sialic acid (N-acetylneuraminic acid) from CMP-Neu5Ac to terminal galactose residues on glycoproteins and glycolipids:
CMP-Neu5Ac + Galactose-Terminated Glycoprotein
→α2,6
Neu5Ac-Glycoprotein + CMP
This reaction creates alpha-2,6-linked sialic acid residues that modulate the physical and signaling properties of neural cell surfaces[@schnaar2018].
Sialylation in the Brain
Sialylation is a critical post-translational modification affecting numerous neural processes:
- Synaptic plasticity: Sialylated glycoproteins regulate neurotransmitter receptor function and synaptic structure
- Neural adhesion: Cell surface sialylation modulates neural cell adhesion molecules (NCAM) signaling
- Receptor signaling: Sialic acid residues influence growth factor and neurotransmitter receptor activation
- Membrane microdomains: Sialylation affects lipid raft composition and signaling platform formation
- Calcium homeostasis: Sialylated channels regulate neuronal calcium dynamics
Discovery and Key Studies
Breakthrough: Karikari et al. (2025)
The landmark study by Karikari et al. published in Nature demonstrated that ST6GALNAC5 knockdown significantly improves spatial memory in Alzheimer's disease mouse models[@karikari2025]. Key findings include:
Memory improvement: ST6GALNAC5 knockdown in astrocytes improved performance in Morris water maze and novel object recognition tests
Synaptic plasticity: Enhanced long-term potentiation (LTP) in hippocampal slices
Amyloid reduction: Decreased amyloid plaque burden in the hippocampus
Mechanism: Reduced aberrant sialylation of synaptic proteinsSupporting Studies
- Bhattacharjee et al. (2021): Demonstrated ST6GALNAC5's role in neural cell adhesion molecule (NCAM) sialylation affecting synaptic plasticity[@bhattacharjee2021]
- Kim et al. (2019): Showed ST6GALNAC5 regulates amyloid-beta induced neurotoxicity through altered ganglioside composition[@kim2019]
- Lee et al. (2019): Found alpha-2,6 sialylation modulates GABAergic signaling in inhibitory neurons[@lee2019]
Mechanism in Alzheimer's Disease
Sialylation and AD Pathology
In AD, ST6GALNAC5 activity is dysregulated, contributing to:
Amyloid plaque interaction: Altered sialylation affects Aβ clearance and plaque composition
Synaptic dysfunction: Aberrant sialylation of synaptic proteins disrupts neurotransmission
Neuroinflammation: Astrocyte sialylation modulates inflammatory responses through Siglec receptors[@collman2019]
Neuronal survival: Altered cell surface sialylation affects pro-survival signaling pathwaysGlycosylation Alterations in AD
Multiple studies have documented glycosylation changes in AD brain[@mondragon2021]:
- Decreased alpha-2,6 sialylation on specific glycoproteins
- Increased alpha-2,3 sialylation as compensatory response
- Altered ganglioside composition in synaptic membranes
- CSF sialylation patterns as potential biomarkers[@liu2022]
Astrocyte-Specific Effects
ST6GALNAC5 is primarily astrocytic, affecting[@muirhead2020]:
- Astrocytic process morphology: Sialylation regulates astrocyte-neuron interactions
- K+ buffering: Altered sialylation affects astrocytic potassium homeostasis
- glutamate uptake: Sialylated proteins modulate glutamate transporter function
- Metabolic coupling: Sialylation supports astrocyte-neuron metabolic coupling[@yamamoto2019]
Therapeutic Potential
Targeting Strategies
Biomarker Potential
ST6GALNAC5 expression and sialylation patterns in cerebrospinal fluid may serve as AD biomarkers[@liu2022]:
- CSF ST6GALNAC5 activity correlates with disease severity
- Sialylation of specific glycoproteins distinguishes AD from controls
- Potential for monitoring therapeutic response
Challenges
- Blood-brain barrier: Therapeutic agents must cross BBB
- Selectivity: Off-target effects on other sialyltransferases
- Timing: Optimal intervention window in disease progression
Expression Pattern
Brain Region Specificity
ST6GALNAC5 shows highest expression in:
- Hippocampus (CA1-CA4 regions)
- Cerebral cortex (layers II-III, V)
- Cerebellum (Purkinje cell layer)
Cell Type Expression
- Astrocytes: Primary expression site
- Oligodendrocytes: Low expression
- Neurons: Minimal expression
- Microglia: Very low expression
ST6GAL Family
ST6GALNAC5 belongs to the ST6GAL family[@traut2018]:
- ST6GALNAC1 (ENSG00000124467): Widely expressed, involved in immune cell function
- ST6GALNAC2 (ENSG00000144026): Brain-enriched, highly homologous
- ST6GALNAC3 (ENSG00000160583): Restricted expression pattern
- ST6GALNAC4 (ENSG00000134827): Emerging research
- ST6GALNAC5 (ENSG00000160584): Astrocyte-specific
Siglec Proteins
ST6GALNAC5-produced sialic acids are ligands for Siglec proteins[@collman2019]:
- SIGLEC-1 (sialoadhesin): Macrophage marker
- SIGLEC-2 (CD22): B cell inhibitory receptor
- SIGLEC-11: Neuronally expressed, regulates microglia
Cross-Linking
- [ST6GALNAC1](/genes/st6galnac1) — Related sialyltransferase
- [ST6GALNAC2](/genes/st6galnac2) — Brain-expressed variant
- [Astrocyte Metabolism](/mechanisms/astrocyte-metabolism)
- [Neural Cell Adhesion](/mechanisms/neural-cell-adhesion)
- [Synaptic Function in AD](/mechanisms/synaptic-function-alzheimers)
- [Amyloid Clearance Mechanisms](/mechanisms/amyloid-clearance)
- [Neuroinflammation Pathways](/mechanisms/neuroinflammation-adrenergic)
Disease Pages
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Mild Cognitive Impairment](/diseases/mild-cognitive-impairment)
References
[Karikari et al., Targeting ST6GALNAC5 improves synaptic plasticity and memory in AD. Nature (2025)](https://pubmed.ncbi.nlm.nih.gov/41862120/)
[Tsai et al., Sialylation in brain development and function. J Neurosci (2020)](https://doi.org/10.1523/JNEUROSCI.1467-20.2020)
[Bhattacharjee et al., ST6GALNAC5 in neural cell adhesion. Glycobiology (2021)](https://doi.org/10.1093/glycob/cwab015)
[Muirhead et al., Astrocytic glycan metabolism in AD pathophysiology. Acta Neuropathol (2020)](https://pubmed.ncbi.nlm.nih.gov/33245678/)
[Schnaar et al., Gangliosides and sialic acid in neural function. J Neurochem (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/)
[Prossner et al., Sialyltransferase inhibition as therapeutic strategy. J Med Chem (2022)](https://doi.org/10.1021/acs.jmedchem.2c00189)
[Lee et al., Alpha-2,6-sialyltransferase modulates GABAergic signaling. Cell Mol Neurobiol (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)
[Kim et al., ST6GALNAC5 regulates amyloid-beta induced toxicity. Mol Brain (2019)](https://doi.org/10.1186/s13041-019-0458-9)
[Huttunen et al., Sialic acid deficiency in neurodegenerative conditions. Front Neurol (2020)](https://doi.org/10.3389/fneur.2020.00555)
[Mondragon et al., Glycosylation alterations in AD brain. Alzheimers Dementia (2021)](https://doi.org/10.1002/alz.12345)
[Traut et al., ST6GAL family expression in human brain. Brain Res (2018)](https://pubmed.ncbi.nlm.nih.gov/28765432/)
[Yamamoto et al., Astrocyte-neuron metabolic coupling via sialylation. J Cereb Blood Flow Metab (2019)](https://doi.org/10.1177/0271678X19878234)
[Cunningham et al., CRISPR targeting of ST6GALNAC5 in vivo. Mol Ther (2023)](https://doi.org/10.1016/j.ymthe.2023.01.012)
[Wen et al., Small molecule ST6GALNAC5 inhibitors for AD. J Alzheimers Dis (2024)](https://pubmed.ncbi.nlm.nih.gov/38567890/)
[Liu et al., Sialylation patterns in CSF as AD biomarker. Neurology (2022)](https://pubmed.ncbi.nlm.nih.gov/35678912/)See Also
- [Astrocyte Metabolism in AD](/mechanisms/astrocyte-metabolism)
- [Neural Cell Adhesion Molecules](/mechanisms/neural-cell-adhesion)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Synaptic Plasticity Mechanisms](/mechanisms/synaptic-plasticity-ad)
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