PRMT5
| | | [1]
|---|---| [2]
| Full Name | Protein Arginine Methyltransferase 5 | [3]
| Gene Symbol | PRMT5 | [4]
| Aliases | SKB1, JBP1, IBP72, HRMT1L5 | [5]
| Chromosome | 14q11.2 | [6]
| Gene Type | Protein-coding | [7]
| OMIM | 604045 | [8]
| UniProt | O14744 |
| HGNC | 20601 |
| Entrez Gene | 10419 |
| Ensembl | ENSG00000100462 |
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, Parkinson's disease, and amyotrophic lateral sclerosis.
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.
PRMT5 symmetrically dimethylates histone H4R3 (H4R3me2s), creating a repressive chromatin mark that recruits DNMT3A for 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-mediated H3K27me3 to reinforce polycomb-mediated gene silencing.
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, PRMT5-dependent splicing regulation controls alternative exon inclusion in synaptic genes, including MAPT (tau) and NRXN1. Loss of PRMT5 leads to widespread splicing defects that compromise neuronal function.
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.
PRMT5 methylates EGFR, PI3K, and NF-κB pathway components, modulating growth factor signaling and inflammatory responses. In microglia, PRMT5 regulates NF-κB-driven cytokine expression, positioning it as a key modulator of neuroinflammation.
PRMT5 expression is reduced in AD brain tissue, particularly in the hippocampus and entorhinal cortex. Decreased PRMT5 activity leads to aberrant splicing of MAPT, increasing production of 4-repeat tau isoforms that promote 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 promoter regions leads to transcriptional de-repression of β-secretase, increasing amyloid-β production.
PRMT5 methylates α-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.
PRMT5-mediated methylation of FUS and 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.
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, 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 reveals cell-type-specific regulation with highest expression in oligodendrocyte precursor cells during myelination.
| Variant | Type | Association | Reference |
|---|---|---|---|
| rs17030908 | Intronic SNP | Nominal association with AD risk in GWAS | Karch et al., 2014 |
| rs56221703 | Missense (R368H) | Reduced methyltransferase activity | Antonysamy et al., 2012 |
| rs2244552 | Promoter | Altered PRMT5 expression in brain tissue | GTEx Consortium, 2020 |
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:
Antonysamy et al. Crystal structure of the human PRMT5:MEP50 complex (2012). 2012. ↩︎
Blanc & Richard, Arginine methylation: the coming of age (2017). 2017. ↩︎
Andreu-Pérez et al. Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude (2011). 2011. ↩︎
Zhao et al. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A coupling histone and DNA methylation (2009). 2009. ↩︎
Braun et al. Symmetric dimethylation of arginine residues in FUS linked to ALS (2021). 2021. ↩︎
Karkhanis et al. Versatility of PRMT5-induced methylation in growth control and development (2011). 2011. ↩︎
Deng et al. PRMT1 and PRMT5 regulate distinct aspects of RNA splicing and neuronal differentiation (2020). 2020. ↩︎
Burgos et al. Histone H2A monoubiquitination and PRMT5 symmetric dimethylation cooperate in polycomb gene silencing (2015). 2015. ↩︎