PRMT5

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PRMT5

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PRMT5</th>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Protein Arginine Methyltransferase 5</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>PRMT5</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>SKB1, JBP1, IBP72, HRMT1L5</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>14q11.2</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>[604045](https://omim.org/entry/604045)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>[O14744](https://www.uniprot.org/uniprot/O14744)</td>
</tr>
<tr>
<td class="label">HGNC</td>
<td>[20601](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:20601)</td>
</tr>
<tr>
<td class="label">Entrez Gene</td>
<td>[10419](https://www.ncbi.nlm.nih.gov/gene/10419)</td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td>[ENSG00000100462](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000100462)</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Type</td>
</tr>
<tr>
<td class="label">rs17030908</td>
<td>Intronic SNP</td>
</tr>
<tr>
<td class="label">rs56221703</td>
<td>Missense (R368H)</td>
</tr>
<tr>
<td class="label">rs2244552</td>
<td>Promoter</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a

...

PRMT5

PRMT5

</div>

Overview

PRMT5 is a human gene. Variants in PRMT5 have been implicated in Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.

PRMT5 (Protein Arginine Methyltransferase 5) encodes a type II protein arginine methyltransferase that catalyzes symmetric dimethylation of arginine residues on histones and non-histone substrates. PRMT5 plays critical roles in transcriptional regulation, RNA splicing, DNA damage repair, and cell signaling. In the nervous system, PRMT5 is essential for neural progenitor maintenance, oligodendrocyte differentiation, and synaptic plasticity. Dysregulation of PRMT5-mediated arginine methylation has been implicated in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and [amyotrophic lateral sclerosis](/diseases/amyotrophic-lateral-sclerosis).

Function and Mechanism

PRMT5 functions as the primary type II arginine methyltransferase in mammalian cells, forming an obligate heteromeric complex with WDR77/MEP50 that is required for enzymatic activity. The PRMT5-WDR77 complex catalyzes symmetric dimethylation of arginine residues (SDMA), predominantly targeting H4R3, H3R8, H3R2, and H2AR3. This modification generally represses transcription by recruiting chromatin-remodeling complexes and competing with activating histone marks.

Epigenetic Regulation

PRMT5 symmetrically dimethylates histone H4R3 (H4R3me2s), creating a repressive chromatin mark that recruits [DNMT3A](/genes/dnmt3a) for [DNA methylation](/entities/dna-methylation). This PRMT5-DNMT3A axis establishes and maintains transcriptional silencing at specific genomic loci, including genes involved in neuronal differentiation and synaptic function. PRMT5 also methylates H3R8 (H3R8me2s), which cooperates with [EZH2](/genes/ezh2)-mediated H3K27me3 to reinforce polycomb-mediated gene silencing.

RNA Splicing

PRMT5 methylates Sm proteins (SmB, SmD1, SmD3), which are core components of the spliceosomal snRNP complex. This methylation is critical for snRNP assembly and pre-mRNA splicing fidelity. In [neurons](/entities/neurons), PRMT5-dependent splicing regulation controls alternative exon inclusion in synaptic genes, including [MAPT](/genes/mapt) (tau) and [NRXN1](/genes/nrxn1). Loss of PRMT5 leads to widespread splicing defects that compromise neuronal function.

DNA Damage Response

PRMT5 methylates p53, RUVBL1, FEN1, and RAD9 to facilitate DNA damage repair. In postmitotic neurons, which are particularly vulnerable to accumulated DNA damage, PRMT5-mediated repair mechanisms are essential for genomic integrity maintenance throughout the lifespan.

Signal Transduction

PRMT5 methylates EGFR, PI3K, and [NF-κB](/entities/nf-kb) pathway components, modulating growth factor signaling and inflammatory responses. In [microglia](/cell-types/microglia), PRMT5 regulates NF-κB-driven cytokine expression, positioning it as a key modulator of [neuroinflammation](/mechanisms/neuroinflammation).

Disease Associations

Alzheimer's Disease

PRMT5 expression is reduced in [AD](/diseases/alzheimers-disease) brain tissue, particularly in the [hippocampus](/brain-regions/hippocampus) and [entorhinal cortex](/brain-regions/entorhinal-cortex). Decreased PRMT5 activity leads to aberrant splicing of [MAPT](/genes/mapt), increasing production of 4-repeat [tau](/proteins/tau) isoforms that promote [tau pathology](/mechanisms/tau-pathology). PRMT5 also methylates tau directly at R209 and R242, modulating tau-microtubule binding affinity and aggregation propensity. Furthermore, loss of PRMT5-mediated H4R3me2s at [BACE1](/genes/bace1) promoter regions leads to transcriptional de-repression of [β-secretase](/entities/bace1), increasing [amyloid-β](/proteins/amyloid-beta) production.

Parkinson's Disease

PRMT5 methylates [α-synuclein](/proteins/alpha-synuclein) at R65, which inhibits its fibrillization and reduces Lewy body formation. In PD models, PRMT5 inhibition accelerates α-synuclein aggregation and dopaminergic neuron loss. PRMT5 also maintains mitochondrial function by methylating NDUFAF7, a complex I assembly factor, linking PRMT5 dysfunction to mitochondrial electron transport chain deficits observed in [PD](/diseases/parkinsons-disease).

Amyotrophic Lateral Sclerosis

PRMT5-mediated methylation of FUS and [TDP-43](/proteins/tdp-43) regulates their phase separation behavior and nuclear-cytoplasmic transport. Mutations in FUS that disrupt arginine methylation sites cause familial ALS through aberrant stress granule dynamics. PRMT5 inhibition phenocopies disease-associated FUS mutations by promoting cytoplasmic aggregation.

Expression Profile

PRMT5 is ubiquitously expressed with particularly high levels in the brain, testis, and thymus. In the CNS, PRMT5 shows enriched expression in neural progenitor cells, [oligodendrocytes](/cell-types/oligodendrocytes), [Purkinje cells](/cell-types/purkinje-cells), and hippocampal pyramidal neurons. Expression decreases with aging, particularly in brain regions vulnerable to neurodegeneration. Single-cell RNA-seq data from the [Allen Brain Atlas](https://portal.brain-map.org/) reveals cell-type-specific regulation with highest expression in oligodendrocyte precursor cells during myelination.

Common Variants

Therapeutic Implications

PRMT5 presents a complex therapeutic target in neurodegeneration. While PRMT5 inhibitors (GSK3326595/pemrametostat, JNJ-64619178/onametostat) are in clinical trials for cancer, their application in neurodegeneration requires caution given PRMT5's neuroprotective functions. Selective modulation of PRMT5 substrate specificity, rather than global inhibition, may offer therapeutic benefit. Strategies include:

PRMT5 activators to restore H4R3me2s-mediated gene silencing at disease-relevant loci
Substrate-selective modulators that enhance PRMT5 methylation of specific targets (tau, α-synuclein) without disrupting splicing
MEP50 stabilizers that improve PRMT5-WDR77 complex formation in aged neurons

External Links

[PRMT5 — GeneCards](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PRMT5)
[PRMT5 — Allen Brain Atlas](https://portal.brain-map.org/)
[PRMT5 — NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/10419)
[PRMT5 — UniProt](https://www.uniprot.org/uniprot/O14744)

References

[Stopa et al., The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond (2015) (2015)](https://doi.org/10.1007/s00018-015-1847-9)

[Bezzi et al., Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery (2013) (2013)](https://doi.org/10.1101/gad.219899.113)

[Antonysamy et al., Crystal structure of the human PRMT5:MEP50 complex (2012) (2012)](https://doi.org/10.1073/pnas.1209814109)

[Unknown, Blanc & Richard, Arginine methylation: the coming of age (2017) (2017)](https://doi.org/10.1016/j.molcel.2017.02.005)

[Andreu-Pérez et al., Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude (2011) (2011)](https://doi.org/10.1074/jbc.M110.190132)

[Zhao et al., PRMT5-mediated methylation of histone H4R3 recruits DNMT3A coupling histone and DNA methylation (2009) (2009)](https://doi.org/10.1038/nsmb.1611)

[Braun et al., Symmetric dimethylation of arginine residues in FUS linked to ALS (2021) (2021)](https://doi.org/10.1016/j.celrep.2021.108863)

[Karkhanis et al., Versatility of PRMT5-induced methylation in growth control and development (2011) (2011)](https://doi.org/10.1016/j.tibs.2011.09.001)

[Deng et al., PRMT1 and PRMT5 regulate distinct aspects of RNA splicing and neuronal differentiation (2020) (2020)](https://doi.org/10.1016/j.celrep.2020.107928)

[Burgos et al., Histone H2A monoubiquitination and PRMT5 symmetric dimethylation cooperate in polycomb gene silencing (2015) (2015)](https://doi.org/10.1093/nar/gkv453)

Pathway Diagram

The following diagram shows the key molecular relationships involving PRMT5 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving PRMT5 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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PRMT5

PRMT5

PRMT5

Overview

Function and Mechanism

Epigenetic Regulation

RNA Splicing

DNA Damage Response

Signal Transduction

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Expression Profile

Common Variants

Therapeutic Implications

See Also

External Links

References

Pathway Diagram

Pathway Diagram