PPP2R5A (Protein Phosphatase 2A Regulatory Subunit B56 Alpha)
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<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">PPP2R5A Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>PPP2R5A</td></tr>
<tr><td><strong>Full Name</strong></td><td>Protein Phosphatase 2A Regulatory Subunit B56 Alpha</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>1q41</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[5525](https://www.ncbi.nlm.nih.gov/gene/5525)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[601653](https://www.omim.org/entry/601653)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000100994</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q16586](https://www.uniprot.org/uniprot/Q16586)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Cancer</td></tr>
</table>
</div>
Overview
The PPP2R5A gene encodes the alpha isoform of the B56 regulatory subunit of protein phosphatase 2A (PP2A), one of the most abundant serine/threonine phosphatases in eukaryotic cells. PP2A holoenzymes containing the B56α subunit play critical roles in regulating cell cycle progression, DNA damage responses, signal transduction pathways, and neuronal function. PP2A-B56α is particularly important in the nervous system, where it governs synaptic plasticity, learning and memory, and the phosphorylation state of proteins central to neurodegeneration.
Gene Structure
The PPP2R5A gene is located on chromosome 1q41 and encodes a protein of approximately 526 amino acids with a molecular weight of ~57 kDa. The gene contains multiple exons and gives rise to multiple splice variants with distinct tissue distribution patterns. The B56 family consists of five related genes (PPP2R5A-E) encoding related regulatory subunits, each producing multiple isoforms through alternative splicing.
Protein Structure and Function
PP2A exists as a heterotrimeric complex with a catalytic subunit (PP2A-C), a scaffold subunit (PP2A-A), and a regulatory subunit (PP2A-B) that determines substrate specificity and cellular localization. The B56α subunit belongs to the B56 family of regulatory subunits, characterized by N-terminal conserved repeat sequences, a C-terminal region involved in dimerization with PP2A-C, and multiple phosphorylation sites regulating subunit interactions.
PP2A-B56α-containing holoenzymes have unique functions including substrate specificity for tau protein at multiple AD-relevant sites, p53 and CHK1 in DNA damage response, β-catenin in Wnt signaling, and AMPA and NMDA receptors in neurons.
Biological Functions
PP2A-B56α plays a central role in cell cycle control by dephosphorylating retinoblastoma protein, regulating cyclin-dependent kinase activity, controlling E2F transcription factor activation, modulating CHK1 and CHK2 activity, and regulating entry into mitosis.
In DNA damage response, PP2A-B56α is essential for checkpoint signaling through ATM and ATR pathways, dephosphorylating CHK1, regulating p53 activation, and controlling cell cycle arrest.
PP2A-B56α critically regulates Wnt/β-catenin signaling by dephosphorylating β-catenin, controlling TCF/LEF transcription factor activity, and regulating Wnt target gene expression.
In the nervous system, PP2A-B56α modulates AMPA receptor trafficking, regulates NMDA receptor function, controls LTP and LTD, and is essential for learning and memory formation. It dephosphorylates tau at AD-relevant sites including Ser202, Thr205, Ser396, and Ser404.
Role in Alzheimer's Disease
Multiple studies demonstrate that PP2A activity is significantly reduced in AD brains, with the catalytic subunit levels decreased, regulatory subunit alterations, post-translational modifications causing hyperphosphorylation/inactivation, and endogenous PP2A inhibitors increased. The loss of PP2A-B56α function contributes directly to tau hyperphosphorylation at multiple sites, NFT formation, synaptic loss, and neurodegeneration.
PP2A activation represents a promising therapeutic strategy through small molecule activators, inhibitor blockade, and gene therapy increasing B56α expression.
Role in Parkinson's Disease
PP2A-B56α also plays a role in Parkinson's disease by dephosphorylating α-synuclein at Ser129, with altered PP2A activity potentially contributing to α-synuclein pathology. PP2A-B56α also regulates mitochondrial quality control through the PINK1/Parkin pathway, controls mitochondrial dynamics, and regulates apoptosis signaling.
See Also
- [PP2A Protein](/proteins/pp2a)
- [PPP2CA Gene](/genes/pp2ca)
- [Tau Protein](/proteins/tau)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
References
[Janssens et al., PP2A: a highly regulated family (2005)](https://doi.org/10.1042/BJ20050050)
[Sontag et al., PP2A and Alzheimer's disease (2014)](https://doi.org/10.3233/RNN-139003)
[Xu et al., B56 subunit structure (2006)](https://doi.org/10.1016/j.tcb.2006.09.007)
[Schmidt et al., B56 cellular functions (2002)](https://doi.org/10.1083/jcb.200201134)
[Yeh et al., PP2A in cell cycle (2001)](https://doi.org/10.1101/gad.945701)
[Janssens et al., PP2A in DNA damage (2008)](https://doi.org/10.1016/j.tcb.2008.04.004)
[Seeling et al., PP2A in Wnt signaling (1999)](https://doi.org/10.1126/science.283.5406.1189)
[Wong et al., PP2A in mTOR and autophagy (2015)](https://doi.org/10.1016/j.cellsig.2015.02.017)
[Nichols et al., PP2A in synaptic plasticity (2005)](https://doi.org/10.1111/j.1460-9568.2005.04226.x)
[Liu et al., PP2A-B56α in tauopathy (2021)](https://doi.org/10.1007/s00401-021-02316-4)
[Gong et al., PP2A and tau phosphorylation (2020)](https://doi.org/10.3233/JAD-200100)
[Chen et al., PP2A dysfunction in AD (2019)](https://doi.org/10.1016/j.neurobiolaging.2018.12.015)
[Martin et al., PP2A in AD (2013)](https://doi.org/10.1016/j.pneurobio.2013.06.007)
[Soni et al., PP2A in PD (2019)](https://doi.org/10.1186/s13024-019-0335-9)