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PRMT3-mediated Arginine Methylation: A Targetable Mechanism to Treat Tauopathies?

By Stuart P. Atkinson, Ph.D.

February 26, 2026

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The How of Tau: Does an Epigenetic PRMT3-associated Mechanism Underpin Neurodegenerative Disease?

The abnormal accumulation of hyperphosphorylated tau as aggregates in neurons characterizes a group of neurodegenerative diseases known as "tauopathies" (Creekmore et al. and Spillantini & Goedert), which include primary tauopathies such as primary age-related tauopathy (PART) (Crary et al.) and secondary tauopathies such as Alzheimer's disease (AD). As the therapeutic targeting of the tau protein (Congdon et al.) and well-known upstream drivers of tau phosphorylation (Zheng et al.) remain problematic, a deeper understanding of the mechanisms driving abnormal tau hyperphosphorylation – which disrupts normal binding to microtubules, reduces solubility, and promotes self-aggregation (Alonso et al.) - may yield novel targets for more efficient therapeutic interventions in tauopathy patients. While PART and AD share similarities regarding tau pathology, tau phosphorylation levels in the entorhinal cortex (where pathology first emerges) in PART patients can exceed those observed in AD patients (Zhang et al. and Jellinger & Attems); furthermore, PART patients lack comorbidities and amyloid plaques (as compared to AD patients) (Yoshida et al., Bell et al., and Jack et al.), removing some of the potential interfering variables from any potential analyses. These previous studies prompted researchers led by Xia Wang, Chao Ma, and Wei Ge (Peking Union Medical College) to attempt to "zone in" on the factors driving the differences in the levels of tau phosphorylation in the entorhinal cortex between AD and PART patients and, as such, advance our understanding of disease mechanisms and potentially identify novel therapeutic targets. The results of these analyses, published recently in Advanced Science, now identify protein arginine methyltransferase 3 (PRMT3) - a type I PRMT that catalyzes asymmetric arginine methylation (Guccione & Richard) - as a critical driver of tau hyperphosphorylation (Liu et al.). As such, this discovery suggests that an epigenetic mechanism underpins the development of tauopathies and that a targeted epigenetic therapeutic strategy may represent a way forward for patients suffering from neurodegenerative disease.

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Towards A Mechanistic Understanding of the Link Between PRMT3 and Tau Hyperphosphorylation

Initial comparative immunohistochemical analyses of samples from PART and AD patients from the National Human Brain Bank for Development and Function (selected to minimize the impact of confounding factors) revealed a significantly greater area covered by hyperphosphorylated tau in the entorhinal cortex of PART patients. Evaluating previous transcriptomic data to identify factors that promoted tau hyperphosphorylation (Luo et al. and Liu et al.) subsequently highlighted PRMT3 as a potentially important driver associated with PART. In confirmation of this link, elevated PRMT3 expression in entorhinal cortex neurons in PART patients correlated with increased levels of asymmetric dimethylation of histone H4 at arginine 3 (H4R3me2a), suggesting that PRMT3-mediated H4R3me2a associates with tau hyperphosphorylation. Of note, H4R3me2a represents a permissive histone modification linked to transcriptional activation (Guccione et al. and Wang et al.). Subsequent in vivo analyses employed Tau P301S transgenic mice (PS19), which overexpress human tau carrying the P301S mutation and display tau pathology localized to the hippocampus and entorhinal cortex and, as such, closely mirror the early distribution of tau pathology observed in PART (Crary et al. and Yashima et al.). This approach demonstrated that neuron-specific, virally mediated overexpression of PRMT3 in the entorhinal cortex led to increased tau hyperphosphorylation and worsened cognitive deficits.

Further confirmatory explorations of this exciting link next revealed that: i) PRMT3 knockdown reduced H4R3me2a and tau phosphorylation levels, ii) PRMT3 overexpression increased H4R3me2a and tau phosphorylation levels, and iii) treatment with a potent, selective, and non-competitive PRMT3 inhibitor (SGC707) reduced H4R3me2a and tau phosphorylation levels in a dose-dependent manner. Furthermore, experiments using a catalytically inactive PRMT3 mutant (unable to add H4R3me2a) did not affect tau phosphorylation levels, suggesting that PRMT3 positively regulates tau phosphorylation by asymmetrically dimethylating histone arginine residues.

But how?! Combining RNA-seq and ChIP-seq to identify expressed genes with H4R3me2a-modified promoter sequences initially failed to identify any relevant protein-coding candidates; therefore, the study asked whether micro(mi)RNAs were the answer. A range of studies have reported how histone methylation can regulate miRNA expression (Mallappa et al., Lee et al., and Qi et al.), and that PRMT3 can activate miR-3648 expression by catalyzing the addition of H4R3me2a to the gene promoter (Min et al.). Analysis of the data from this new study identified the MIR448 gene (miR-448) as a candidate gene expressed in response to increasing levels of H4R3me2a. Previous studies provided a link between miR-448 and disease, with significant roles in tumorigenesis and cardiomyopathy described (Li et al. and Kyrychenko et al.). Here, the overexpression of a miR-448 mimic and treatment with a miR-448 inhibitor significantly increased and decreased tau phosphorylation, respectively. Finally, analysis of downstream targets of miR-448 revealed that this miRNA reduced levels of the IGF1R gene (insulin-like growth factor 1 receptor) (Wang et al. and Liu et al.), which, in turn, induced tau hyperphosphorylation by enhancing glycogen synthase kinase-3 beta (GSK3β) activity (Cardoso et al., Cheng et al., and Yuste & Bonhoeffer).

The final part of the study moved back to in vivo analyses in PS19 tauopathy mice; these assays confirmed that PRMT3 inhibition via intraperitoneal injections of SGC707 reduced tau hyperphosphorylation and cognitive impairment by decreasing H4R3me2a levels at the MIR448 promoter, thereby suppressing miR-448 expression, increasing IGF1R levels, and reducing GSK3β activity. Overall, these data highlight the therapeutic promise of targeting PRMTs/arginine methylation in patients with PART and potentially other tauopathies.

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PRMT3 and Arginine Methylation: A New Target for Tauopathy Treatment?

Overall, these data identify PRMT3 as a critical driver of tau hyperphosphorylation in PART - primary age-related tauopathy - and a potentially exciting therapeutic target for PART and, by extension, additional tauopathies such as AD; furthermore, this study underscores the general importance of arginine methylation as an epigenetic regulatory mechanism. To end, this research employed a histone H4R3me2a (asymmetric) antibody from Active Motif for ChIP and Western blotting; however, Active Motif also offers additional PRMT antibodies and proteins that could support your research aims!

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About the author

Stuart P. Atkinson, Ph.D.

Stuart was born and grew up in the idyllic town of Lanark (Scotland). He later studied biochemistry at the University of Strathclyde in Glasgow (Scotland) before gaining his Ph.D. in medical oncology; his thesis described the epigenetic regulation of the telomerase gene promoters in cancer cells. Following Post-doctoral stays in Newcastle (England) and Valencia (Spain) where his varied research aims included the exploration of epigenetics in embryonic and induced pluripotent stem cells, Stuart moved into project management and scientific writing/editing where his current interests include polymer chemistry, cancer research, regenerative medicine, and epigenetics. While not glued to his laptop, Stuart enjoys exploring the Spanish mountains and coastlines (and everywhere in between) and the food and drink that it provides!

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