Phosphorylated Tau at Threonine 231 (p-tau231)

Phosphorylated Tau at Threonine 231 (p-tau231)

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">p-tau231 — Phosphorylated Tau at Threonine 231</th></tr>
<tr><td><b>Gene</b></td><td>[MAPT](/genes/mapt)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P10636](https://www.uniprot.org/uniprot/P10636)</td></tr>
<tr><td><b>Phosphorylation Site</b></td><td>Threonine 231 (T231)</td></tr>
<tr><td><b>Molecular Weight</b></td><td>45-65 kDa (isoform-dependent)</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Axons, microtubule-associated</td></tr>
<tr><td><b>Protein Family</b></td><td>Microtubule-associated protein (MAP) family</td></tr>
<tr><td><b> kinases</b></td><td>[GSK-3β](/entities/gsk3-beta), [CDK5](/proteins/cdk5), MARK</td></tr>
</table>
</div>

Overview

Phosphorylated [Tau](/proteins/tau) at Threonine 231 (p-tau231) is a hyperphosphorylated form of the [Tau protein](/proteins/tau) encoded by the [MAPT](/genes/mapt) gene. Phosphorylation at T231 represents an early and critical event in tau pathogenesis, making p-tau231 one of the most sensitive biomarkers for [Alzheimer's disease](/diseases/alzheimers-disease) and other tauopathies[@ptau2020].

Biological Significance

Why Threonine 231?

The T231 phosphorylation site is particularly important because:

Phosphorylated Tau at Threonine 231 (p-tau231)

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4ea;">p-tau231 — Phosphorylated Tau at Threonine 231</th></tr>
<tr><td><b>Gene</b></td><td>[MAPT](/genes/mapt)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[P10636](https://www.uniprot.org/uniprot/P10636)</td></tr>
<tr><td><b>Phosphorylation Site</b></td><td>Threonine 231 (T231)</td></tr>
<tr><td><b>Molecular Weight</b></td><td>45-65 kDa (isoform-dependent)</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Axons, microtubule-associated</td></tr>
<tr><td><b>Protein Family</b></td><td>Microtubule-associated protein (MAP) family</td></tr>
<tr><td><b> kinases</b></td><td>[GSK-3β](/entities/gsk3-beta), [CDK5](/proteins/cdk5), MARK</td></tr>
</table>
</div>

Overview

Phosphorylated [Tau](/proteins/tau) at Threonine 231 (p-tau231) is a hyperphosphorylated form of the [Tau protein](/proteins/tau) encoded by the [MAPT](/genes/mapt) gene. Phosphorylation at T231 represents an early and critical event in tau pathogenesis, making p-tau231 one of the most sensitive biomarkers for [Alzheimer's disease](/diseases/alzheimers-disease) and other tauopathies[@ptau2020].

Biological Significance

Why Threonine 231?

The T231 phosphorylation site is particularly important because:

Structural Context

T231 is located in the:

• Proline-rich domain (PRR): Residues 151-244
• Adjacent to microtubule-binding repeats (R1-R4)
• Critical hinge region between N-terminal and C-terminal domains

Phosphorylation Biology

Kinases

Multiple kinases phosphorylate T231:

| Kinase | Role | Notes |
|--------|------|-------|
| GSK-3β | Primary | Hyperactive in AD brain |
| CDK5 | Major | Phosphorylates T231 efficiently |
| MARK/PAR-1 | Early event | Involved in tau spreading |

Phosphatases

• [PP2A](/entities/pp2a): Major phosphatase dephosphorylating T231
• PP1: Minor contribution
• Activity reduced in AD brain

Role in Alzheimer's Disease

Pathogenic Mechanisms

• Reduced tau-microtubule binding
• Impaired axonal transport
• Synaptic dysfunction

• p-tau231 promotes paired helical filament formation
• Serves as template for further phosphorylation
• Spreads between connected [neurons](/entities/neurons)

• Loss of neurotrophic support
• Mitochondrial transport defects
• Calcium dysregulation

Spreading Mechanism

p-tau231 serves as a "seed" for prion-like propagation:

• Released from dying neurons
• Taken up by neighboring cells
• Templates further tau pathology

Biomarker Potential

Diagnostic Value

p-tau231 is an early and specific biomarker for AD:

| Feature | p-tau231 | p-tau181 | [p-tau217](/biomarkers/p-tau-217) |
|---------|----------|----------|----------|
| Detectable in preclinical AD | ++ | + | + |
| Specificity for AD vs. other dementias | +++ | ++ | +++ |
| Correlation with tau PET | ++ | ++ | +++ |
| Cerebrospinal fluid | Available | Available | Available |
| Blood-based detection | Emerging | Available | Emerging |

Clinical Applications

• Early Diagnosis: Detectable before clinical symptoms
• Disease Progression: Correlates with cognitive decline
• Treatment Monitoring: Potential biomarker for drug trials

Detection Methods

Established Techniques

• ELISA: Highly sensitive CSF detection
• SIMOA: Ultra-sensitive blood detection
• Western Blot: Semi-quantitative analysis
• Mass Spectrometry: Site-specific quantification

Emerging Technologies

• Single molecule array (Simoa): Picoliter-scale detection
• Immuno-PCR: Enhanced sensitivity
• Blood p-tau231: Under development

Therapeutic Implications

Targeting p-tau231

Challenges

• [Blood-brain barrier](/entities/blood-brain-barrier) penetration
• Kinase inhibitor specificity
• Early intervention timing

Research Directions

• Blood-based p-tau231 detection
• PET ligands for p-tau231
• Understanding kinase-phosphatase balance
• Clinical validation studies

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Tau Protein](/proteins/tau)
• [MAPT Gene](/genes/mapt)
• [p-tau181](/proteins/p-tau181-protein)
• [p-tau217](/proteins/p-tau217-protein)
• [Neurofibrillary Tangles](/mechanisms/tau-pathology)
• [Tau Pathology](/mechanisms/tau-pathology)

External Links

• [UniProt: P10636](https://www.uniprot.org/uniprot/P10636)
• [AlphaFold: P10636](https://alphafold.ebi.ac.uk/entry/P10636)
• [AlzGene: MAPT](https://www.alzgene.org/gene/MAPT)

References