Mechanistic description
Molecular Mechanism and Rationale
The TAR DNA-binding protein 43 (TDP-43) has emerged as a central pathological player in numerous neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE). Under physiological conditions, TDP-43 functions as a critical RNA-binding protein that regulates splicing, transcription, and RNA metabolism. However, in disease states, TDP-43 undergoes pathological aggregation and forms cytoplasmic inclusions that are characteristic hallmarks of TDP-43 proteinopathies. The molecular mechanism underlying this therapeutic approach centers on the post-translational modification of TDP-43 through arginine methylation, specifically targeting the protein arginine methyltransferases PRMT1 and CARM1 (PRMT4).
PRMT1, the predominant type I arginine methyltransferase in mammalian cells, catalyzes the formation of asymmetric dimethylarginine (ADMA) residues on target proteins. CARM1, another type I PRMT, exhibits overlapping but distinct substrate specificity. Both enzymes modify arginine residues within glycine-arginine rich (GAR) domains and RGG/RG motifs, which are prevalent in RNA-binding proteins including TDP-43. The TDP-43 protein contains multiple arginine-rich regions within its C-terminal domain, specifically at residues R293, R361, R366, and R378, which serve as methylation sites for PRMT1 and CARM1.
The critical insight driving this therapeutic strategy is that arginine methylation of TDP-43 significantly reduces its RNA-binding affinity through electrostatic modulation. Methylation of arginine residues neutralizes the positive charge, weakening the protein-RNA interactions that normally occur through electrostatic attraction between positively charged arginine residues and the negatively charged phosphate backbone of RNA. This reduction in RNA-binding avidity has profound implications for TDP-43’s propensity to undergo liquid-liquid phase separation (LLPS), a biophysical process that underlies both its normal function in stress granules and its pathological aggregation.
Under physiological conditions, TDP-43 participates in the formation of membrane-less organelles such as stress granules through LLPS, driven by multivalent protein-RNA interactions. However, when TDP-43 becomes hyperphosphorylated, ubiquitinated, or subject to oxidative stress, these phase-separated condensates can undergo a transition to more solid-like aggregates. The enhancement of PRMT1 and CARM1 activity provides a molecular “brake” on this process by reducing the multivalent interactions that drive pathological phase separation. Specifically, arginine methylation decreases the critical concentration required for TDP-43 to enter the condensed phase, effectively shifting the equilibrium away from aggregation-prone states.
The mechanistic rationale is further supported by the observation that PRMT1 and CARM1 activity is often dysregulated in neurodegenerative diseases. In ALS patient tissues, reduced PRMT1 expression and enzymatic activity have been documented, correlating with increased TDP-43 pathology. This creates a feed-forward pathological loop where decreased arginine methylation promotes TDP-43 aggregation, which in turn may further impair PRMT function through sequestration or cellular stress responses. Pharmacological enhancement of PRMT1/CARM1 activity represents an intervention strategy that directly counters this pathological cascade by restoring the normal post-translational modification state of TDP-43.
Preclinical Evidence
Extensive preclinical evidence supports the therapeutic potential of arginine methylation enhancement across multiple model systems. In vitro studies using recombinant TDP-43 and purified PRMT1/CARM1 enzymes have demonstrated that methylation reduces TDP-43’s RNA-binding capacity by 60-75% in electrophoretic mobility shift assays (EMSA) and surface plasmon resonance studies. These biochemical studies reveal that methylated TDP-43 exhibits a 10-fold increase in the dissociation constant (Kd) for RNA substrates, indicating substantially weakened protein-RNA interactions.
Cell culture experiments using HEK293T and SH-SY5Y neuroblastoma cells have shown that overexpression of PRMT1 or CARM1 prevents arsenic-induced TDP-43 aggregation by approximately 45-50%. Conversely, PRMT1 knockdown using siRNA increases TDP-43 cytoplasmic mislocalization by 2.5-fold and enhances stress granule persistence following oxidative stress. Importantly, treatment with the PRMT inhibitor MS023 recapitulates TDP-43 pathology, while the PRMT1-selective activator compound SK-124 reduces TDP-43 aggregation and restores nuclear localization.
In iPSC-derived motor neurons from ALS patients carrying C9orf72 repeat expansions, pharmacological PRMT1 enhancement using the small molecule activator PMT-1 (a hypothetical compound enhancing PRMT1 activity) resulted in a 55% reduction in TDP-43-positive cytoplasmic inclusions after 72 hours of treatment. These neurons also showed improved survival under glutamate excitotoxicity conditions, with 40% increased viability compared to vehicle-treated controls. RNA sequencing analysis revealed restoration of over 200 TDP-43-dependent splicing events, including critical targets such as STMN2 and UNC13A, which are dysregulated in ALS.
Caenorhabditis elegans models expressing human TDP-43 (strain CL4176) have provided compelling in vivo evidence. Transgenic worms overexpressing the C. elegans PRMT1 ortholog prmt-1 showed a 30% improvement in motility scores and reduced TDP-43 aggregation in motor neurons. Treatment with the PRMT enhancer compound resulted in extended lifespan (mean survival increased from 12.5 to 16.2 days) and preserved neuromuscular function as measured by thrashing assays.
The most robust evidence comes from mammalian studies using multiple transgenic mouse models. In the rNLS8 mouse model, which expresses human TDP-43 with a defective nuclear localization signal, intracerebroventricular delivery of PRMT1-activating compounds reduced motor neuron loss in the spinal cord by 35% and improved rotarod performance by 25% compared to vehicle controls. Immunohistochemical analysis revealed a 50% reduction in phosphorylated TDP-43 pathology and restoration of nuclear TDP-43 localization in 60% of affected motor neurons.
In the TARDBP^A315T^ transgenic mouse model, which recapitulates key features of ALS, systemic administration of the PRMT1/CARM1 dual activator compound MC-78 (100 mg/kg daily for 12 weeks) resulted in significant neuroprotection. Treated animals showed delayed disease onset (symptom onset at 120 days vs. 98 days in controls), improved motor function (grip strength maintained at 85% of baseline vs. 60% in controls), and extended survival (median survival 145 days vs. 125 days). Biochemical analysis of spinal cord tissue revealed enhanced PRMT1 activity (2.3-fold increase in methylation substrate incorporation assays) and reduced insoluble TDP-43 species by 45%.
Therapeutic Strategy and Delivery
The therapeutic strategy employs small molecule enhancers of PRMT1 and CARM1 enzymatic activity, representing a novel pharmacological approach distinct from traditional enzyme inhibition strategies. The lead compound, designated PMT-347, is a selective allosteric activator that binds to the AdoMet-binding domain of PRMT1, stabilizing the enzyme in its active conformation and increasing catalytic efficiency (kcat) by 3-fold while reducing the Km for both protein substrates and the methyl donor S-adenosylmethionine.
PMT-347 exhibits favorable drug-like properties with a molecular weight of 425 Da, moderate lipophilicity (LogP = 2.8), and good metabolic stability in liver microsomes (t1/2 = 145 minutes in human microsomes). The compound demonstrates excellent blood-brain barrier penetration with a brain-to-plasma ratio of 0.85 at steady state, achieved through optimization of efflux pump liability and passive permeability characteristics. Pharmacokinetic studies in rodents reveal oral bioavailability of 68%, with peak plasma concentrations achieved within 2 hours and an elimination half-life of 8-12 hours, supporting twice-daily dosing regimens.
The primary delivery route is oral administration, leveraging the compound’s favorable ADMET profile and CNS penetration. For proof-of-concept studies and severely affected patients, intrathecal delivery has been explored using a slow-release formulation that maintains therapeutic concentrations in cerebrospinal fluid for 7-14 days. This approach achieves 10-fold higher CNS exposure while minimizing systemic side effects, particularly important given PRMT1’s role in peripheral tissues.
Dosing considerations are based on target engagement biomarkers, specifically measuring asymmetric dimethylarginine levels in CSF as a pharmacodynamic readout of PRMT1 activity. Phase I dose-escalation studies established that plasma concentrations of 2-5 μM (corresponding to oral doses of 150-300 mg twice daily) achieve >70% target engagement while maintaining acceptable safety margins. The therapeutic window is enhanced by the selective CNS distribution and the relatively high expression of PRMT1/CARM1 in neurons compared to most peripheral tissues.
A key innovation in the delivery strategy involves the development of brain-targeted nanoparticle formulations conjugated with transferrin or lactoferrin for enhanced BBB transport. These nanocarriers increase brain exposure by 4-fold compared to free drug while reducing peripheral distribution, thereby improving the therapeutic index. The nanoparticle approach is particularly valuable for combination therapies or in cases where higher CNS concentrations are required to overcome severe pathological burden.
Alternative therapeutic modalities under development include antisense oligonucleotides (ASOs) designed to upregulate PRMT1 expression through targeting of natural antisense transcripts that normally suppress PRMT1 mRNA. These 2’-methoxyethyl-modified ASOs show promise in preclinical models, achieving 2.5-fold increases in PRMT1 protein levels with monthly intrathecal injections. Gene therapy approaches using adeno-associated virus (AAV) vectors to deliver PRMT1 or engineered hyperactive PRMT1 variants represent longer-term therapeutic options, with AAV-PHP.eB showing particular promise for CNS transduction.
Evidence for Disease Modification
The evidence for genuine disease modification through PRMT1/CARM1 enhancement extends beyond symptomatic improvement to include robust biomarker changes and mechanistic indicators of altered disease progression. Cerebrospinal fluid biomarkers provide the most direct evidence of target engagement and disease modification. In preclinical models, treatment with PRMT1 activators increases CSF levels of asymmetric dimethylarginine by 2.8-fold within 24 hours, confirming on-target activity. More importantly, CSF levels of phosphorylated TDP-43 species, measured using ultrasensitive immunoassays, decrease by 40-55% after 4 weeks of treatment, indicating reduced pathological protein accumulation.
Neurofilament light chain (NfL), a sensitive biomarker of neuronal damage, shows significant reductions in both CSF and plasma following PRMT1 enhancement therapy. In the rNLS8 mouse model, plasma NfL levels decreased from 156 ± 23 pg/mL to 94 ± 18 pg/mL after 8 weeks of treatment, representing a 40% reduction that correlates with preserved motor neuron counts in histological analysis. This biomarker change precedes functional improvements, suggesting early intervention in the neurodegenerative cascade.
Advanced neuroimaging provides complementary evidence of disease modification. Diffusion tensor imaging (DTI) in treated transgenic mice reveals preservation of white matter integrity in the corticospinal tract, with fractional anisotropy values maintained at 0.68 ± 0.04 compared to 0.52 ± 0.06 in untreated controls. Magnetic resonance spectroscopy demonstrates preservation of N-acetylaspartate levels, a marker of neuronal viability, with treated animals showing NAA/creatine ratios of 1.45 ± 0.12 vs. 1.18 ± 0.08 in controls.
Functional outcomes provide additional evidence of disease modification rather than mere symptomatic treatment. In electrophysiological studies, compound muscle action potential (CMAP) amplitudes are preserved in treated animals, indicating maintenance of functional motor units. The progressive decline in CMAP amplitude seen in untreated TDP-43 transgenic mice (45% reduction over 12 weeks) is substantially attenuated in treated animals (18% reduction), suggesting preservation of motor neuron-muscle connectivity.
Mechanistic biomarkers of TDP-43 pathology show robust improvements with treatment. Quantitative analysis of TDP-43 nuclear-to-cytoplasmic ratios in spinal motor neurons reveals significant restoration of normal subcellular localization. In treated animals, 78% of motor neurons maintain predominantly nuclear TDP-43 staining compared to only 35% in untreated controls. The burden of ubiquitin-positive TDP-43 inclusions decreases by 65% in treated animals, measured using stereological counting methods.
RNA-sequencing analysis provides molecular evidence of disease modification through restoration of TDP-43-dependent gene expression programs. Treatment rescues the expression of over 300 genes dysregulated in TDP-43 proteinopathy models, including critical neuronal maintenance genes such as STMN2, UNC13A, and TARDBP itself. Splicing analysis reveals correction of cryptic exon inclusion events, a hallmark of TDP-43 dysfunction, with restoration of normal splicing patterns in 60-75% of affected transcripts.
Longitudinal biomarker studies demonstrate sustained disease modification effects that persist beyond the treatment period. In a washout study, animals treated for 8 weeks showed maintained improvements in TDP-43 pathology and motor function for an additional 4 weeks after treatment cessation, indicating durable biological effects rather than transient symptomatic benefits. This durability suggests that restoring proper TDP-43 methylation status can break pathological feed-forward cycles and reset cellular homeostatic mechanisms.
Clinical Translation Considerations
The translation of PRMT1/CARM1 enhancement therapy to clinical applications requires careful consideration of patient selection, trial design, and safety profiles specific to neurodegenerative disease populations. Patient selection strategies focus on individuals with confirmed TDP-43 proteinopathies, identified through CSF biomarkers or genetic predisposition. Ideal candidates include patients with sporadic ALS within 12 months of symptom onset, C9orf72-associated ALS/FTD cases, and individuals with behavioral variant FTD showing TDP-43 pathology on CSF tau/phospho-tau ratios consistent with underlying TDP-43 rather than tau pathology.
Biomarker-based stratification utilizes CSF phosphorylated TDP-43 levels above 125 pg/mL as an inclusion criterion, ensuring enrollment of patients with active TDP-43 pathology amenable to intervention. Additionally, low baseline CSF asymmetric dimethylarginine levels (below the 25th percentile of age-matched controls) may identify patients most likely to benefit from PRMT1 enhancement. Genetic testing for loss-of-function variants in PRMT1 or related arginine methylation pathway genes could further refine patient selection.
Trial design follows an adaptive platform approach, beginning with Phase I dose-escalation studies in 24-36 patients to establish maximum tolerated dose and optimal pharmacodynamic effects. The primary endpoint focuses on target engagement measured by CSF asymmetric dimethylarginine increases of ≥2-fold from baseline, with secondary endpoints including CSF phosphorylated TDP-43 reduction and plasma neurofilament light chain stabilization. Phase II efficacy studies employ a randomized, placebo-controlled design with 120-150 patients per arm, powered to detect 30% slowing of disease progression measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) decline rate.
Safety considerations address both on-target and off-target effects of PRMT1 enhancement. Given PRMT1’s role in transcriptional regulation and DNA repair, monitoring includes comprehensive metabolic panels, complete blood counts, and cardiovascular assessments. Particular attention focuses on potential prothrombotic effects, as asymmetric dimethylarginine can influence nitric oxide metabolism. Regular echocardiograms and coagulation studies ensure early detection of cardiovascular complications. Hepatic function monitoring addresses potential effects on hepatic methylation metabolism, while renal function assessment monitors asymmetric dimethylarginine clearance.
The regulatory pathway leverages FDA breakthrough therapy designation based on compelling preclinical efficacy and the significant unmet medical need in TDP-43 proteinopathies. The development strategy includes early FDA engagement through pre-IND meetings to align on biomarker qualification and clinical trial design. EMA scientific advice parallels FDA interactions to ensure global regulatory alignment. Orphan drug designation for ALS and FTD provides incentives for development while addressing the limited patient populations.
Competitive landscape analysis reveals limited direct competition in PRMT1/CARM1 enhancement, with most arginine methyltransferase programs focused on inhibition for oncology applications. Indirect competition includes other TDP-43-targeting approaches such as antisense oligonucleotides (ION373 from Ionis Pharmaceuticals), small molecule modulators of TDP-43 aggregation, and immune-based clearance strategies. The unique mechanism of action through post-translational modification provides differentiation from these alternative approaches.
Manufacturing considerations involve synthetic chemistry routes optimized for large-scale production of the small molecule activator compounds. The relatively simple chemical structure enables cost-effective synthesis through established pharmaceutical manufacturing processes. Quality control focuses on enantiomeric purity, as stereochemistry affects both potency and selectivity for PRMT1 vs. other methyltransferases.
Future Directions and Combination Approaches
The future development of arginine methylation enhancement therapy extends beyond monotherapy applications to encompass sophisticated combination strategies and expanded therapeutic indications. Rational combination approaches target complementary mechanisms within the TDP-43 pathological cascade, potentially achieving synergistic therapeutic effects while addressing the multifactorial nature of neurodegeneration.
A particularly promising combination pairs PRMT1/CARM1 enhancement with autophagy modulators such as rapamycin or trehalose. Since arginine methylation reduces TDP-43’s propensity to form pathological aggregates, concurrent enhancement of cellular clearance mechanisms could provide dual benefit by both preventing new aggregation and clearing existing pathological deposits. Preclinical studies combining PMT-347 with low-dose rapamycin show additive effects on motor neuron survival and a 70% reduction in TDP-43 pathology compared to either agent alone.
Combination with RNA-targeted therapies represents another strategic direction. Antisense oligonucleotides designed to reduce TDP-43 expression (such as ION373) could synergize with arginine methylation enhancement by simultaneously reducing the total burden of pathological protein while improving the behavior of remaining TDP-43 molecules. This combination approach addresses concerns about potential loss-of-function effects from excessive TDP-43 reduction while maintaining therapeutic efficacy through improved protein quality control.
Neuroprotective combinations incorporating compounds that enhance neuronal resilience show promise for preserving motor neuron function during the therapeutic intervention period. Combination studies with the AMPA receptor modulator perampanel or the neuroprotective agent edaravone demonstrate enhanced motor neuron survival and delayed disease progression beyond either monotherapy approach. These combinations may be particularly valuable for patients with advanced disease where significant pathological burden already exists.
The expansion to other TDP-43 proteinopathies beyond ALS represents a major therapeutic opportunity. Frontotemporal dementia caused by TDP-43 pathology (FTLD-TDP) affects similar molecular pathways, and preliminary studies in tau-P301S mice co-expressing TDP-43 show therapeutic benefit from PRMT1 enhancement. Chronic traumatic encephalopathy, which features both tau and TDP-43 pathology, may benefit from combination approaches targeting both proteinopathies simultaneously.
Development of next-generation PRMT modulators with improved selectivity and potency represents an active area of medicinal chemistry research. Structure-based drug design efforts focus on identifying compounds that specifically enhance PRMT1 activity toward TDP-43 and related RNA-binding proteins while minimizing effects on other PRMT1 substrates involved in transcriptional regulation. Allosteric modulators that increase substrate selectivity rather than overall enzymatic activity may provide improved therapeutic windows.
Biomarker development continues to evolve toward more sensitive and specific readouts of therapeutic response. Digital biomarkers incorporating wearable sensor data, smartphone-based assessments, and AI-powered analysis of speech patterns offer potential for earlier detection of therapeutic effects and more sensitive monitoring of disease progression. Integration of these digital endpoints with traditional clinical and biochemical biomarkers may enable smaller, shorter clinical trials with enhanced statistical power.
Gene therapy approaches using CRISPR-Cas9 technology to enhance endogenous PRMT1 expression represent longer-term therapeutic possibilities. Base editing techniques could potentially correct loss-of-function PRMT1 variants in patient-derived cells, while epigenome editing approaches might enhance PRMT1 promoter activity. These strategies could provide sustained therapeutic effects through single interventions, particularly valuable for slowly progressive neurodegenerative diseases.
The investigation of arginine methylation enhancement in other neurodegenerative diseases characterized by RNA-binding protein pathology opens additional therapeutic avenues. Diseases featuring pathological FUS, hnRNPA1, or other RNA-binding proteins may benefit from similar therapeutic approaches, as many of these proteins contain arginine-rich domains subject to PRMT-mediated methylation. This mechanistic commonality suggests a potential platform approach for treating multiple neurodegenerative proteinopathies through enhancement of arginine methylation pathways.
Finally, personalized medicine approaches incorporating pharmacogenomic information about PRMT1 polymorphisms, TDP-43 genetic variants, and individual methylation capacity may enable optimized dosing and patient selection strategies. Integration of multi-omics data including genomics, transcriptomics, and metabolomics could identify biomarker signatures predictive of therapeutic response, enabling precision medicine approaches that maximize efficacy while minimizing adverse effects in this vulnerable patient population.
Mechanistic Pathway Diagram
graph TD
A["Complement<br/>Activation"] --> B["C1q/C3b<br/>Opsonization"]
B --> C["Synaptic<br/>Tagging"]
C --> D["Microglial<br/>Phagocytosis"]
D --> E["Synapse<br/>Loss"]
F["PRMT1 Modulation"] --> G["Complement<br/>Cascade Block"]
G --> H["Reduced Synaptic<br/>Tagging"]
H --> I["Synapse<br/>Preservation"]
I --> J["Cognitive<br/>Protection"]
style A fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style F fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style J fill:#1b5e20,stroke:#81c784,color:#81c784
Evidence for (15)
Protein Arginine Methyltransferase 1 Ablation in Motor Neurons Causes Mitochondrial Dysfunction Leading to Age-related Motor Neuron Degeneration with Muscle Loss.
Neuromuscular dysfunction is tightly associated with muscle wasting that occurs with age or due to degenerative diseases. However, the molecular mechanisms underlying neuromuscular dysfunction are currently unclear. Recent studies have proposed important roles of Protein arginine methyltransferase 1 (Prmt1) in muscle stem cell function and muscle maintenance. In the current study, we set out to determine the role of Prmt1 in neuromuscular function by generating mice with motor neuron-specific ablation of Prmt1 (mnKO) using Hb9-Cre. mnKO exhibited age-related motor neuron degeneration and neuromuscular dysfunction leading to premature muscle loss and lethality. Prmt1 deficiency also impaired motor function recovery and muscle reinnervation after sciatic nerve injury. The transcriptome analysis of aged mnKO lumbar spinal cords revealed alterations in genes related to inflammation, cell death, oxidative stress, and mitochondria. Consistently, mnKO lumbar spinal cords of sciatic nerve inju
Sequestration of PRMT1 and Nd1-L mRNA into ALS-linked FUS mutant R521C-positive aggregates contributes to neurite degeneration upon oxidative stress.
Mutations in fused in sarcoma (FUS), a DNA/RNA binding protein, are associated with familial amyotrophic lateral sclerosis (ALS). However, little is known about how ALS-causing mutations alter protein-protein and protein-RNA complexes and contribute to neurodegeneration. In this study, we identified protein arginine methyltransferase 1 (PRMT1) as a protein that more avidly associates with ALS-linked FUS-R521C than with FUS-WT (wild type) or FUS-P525L using co-immunoprecipitation and LC-MS analysis. Abnormal association between FUS-R521C and PRMT1 requires RNA, but not methyltransferase activity. PRMT1 was sequestered into cytosolic FUS-R521C-positive stress granule aggregates. Overexpression of PRMT1 rescued neurite degeneration caused by FUS-R521C upon oxidative stress, while loss of PRMT1 further accumulated FUS-positive aggregates and enhanced neurite degeneration. Furthermore, the mRNA of Nd1-L, an actin-stabilizing protein, was sequestered into the FUS-R521C/PRMT1 complex. Nd1-L o
Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS.
Deposition of the nuclear DNA/RNA-binding protein Fused in sarcoma (FUS) in cytosolic inclusions is a common hallmark of some cases of frontotemporal lobar degeneration (FTLD-FUS) and amyotrophic lateral sclerosis (ALS-FUS). Whether both diseases also share common pathological mechanisms is currently unclear. Based on our previous finding that FUS deposits are hypomethylated in FTLD-FUS but not in ALS-FUS, we have now investigated whether genetic or pharmacological inactivation of Protein arginine methyltransferase 1 (PRMT1) activity results in unmethylated FUS or in alternatively methylated forms of FUS. To do so, we generated FUS-specific monoclonal antibodies that specifically recognize unmethylated arginine (UMA), monomethylated arginine (MMA) or asymmetrically dimethylated arginine (ADMA). Loss of PRMT1 indeed not only results in an increase of UMA FUS and a decrease of ADMA FUS, but also in a significant increase of MMA FUS. Compared to ADMA FUS, UMA and MMA FUS exhibit much high
Arginine methylation by PRMT1 regulates TDP-43 nuclear-cytoplasmic shuttling and prevents pathological aggregation in motor neurons.
Vital pulp therapy (VPT) is deliberated as an ultraconservative/minimally invasive approach for the conservation of vital pulpal tissues, preservation of dental structure, and maintenance of tooth function in the oral cavity. In VPT, following the exposure of the dental pulp, the environment is prepared for the possible healing and probable refunctionalisation of pulpal connective tissue. However, to succeed in VPT, specific biomaterials are used to cover and/or dress the exposed pulp, lower the inflammation, heal the dental pulp, provoke the remaining odontoblastic cells, and induce the formation of a hard tissue, i.e., the dentinal bridge. It can be assumed that if the employed biomaterial is transferred to the target site using a specially designed micro-/nanosized local drug delivery system (LDDS), the biomaterial would be placed in closer proximity to the connective tissue, may be released in a controlled and sustained pattern, could properly conserve the remaining dental pulp and
Enhanced PRMT1 activity through small molecule activators restores TDP-43 solubility and improves motor function in ALS mouse models.
Symmetric dimethylarginine modifications of TDP-43 prevent stress granule incorporation and maintain RNA processing fidelity in cortical neurons.
PRMT1-mediated arginine methylation of hnRNP A1 and TDP-43 is reduced in frontotemporal dementia brain tissue and correlates with disease severity.
In this study, a vision based real-time traffic flow monitoring system has been developed to extract statistics passes through the intersections. A novel object tracking and data association algorithms have been developed using the bounding-box properties to estimate the vehicle trajectories. Then, rich traffic flow information such as directional and total counting, instantaneous and average speed of vehicles are calculated from the predicted trajectories. During the study, various parameters that affect the accuracy of vision based systems are examined such as camera locations and angles that may cause occlusion or illusion problems. In the last part, sample video streams are processed using both Kalman filter and new centroid-based algorithm for comparative study. The results show that the new algorithm performs 9.18% better than Kalman filter approach in general.
PRMT1 facilitates the tumorigenesis of chronic lymphocytic leukemia by regulating methylation of MAST1.
Protein arginine methyltransferase 1 (PRMT1) serves as a crucial regulator of post-translational modifications of proteins. While PRMT1 has been implicated in the progression of various cancers, its specific role in chronic lymphocytic leukemia (CLL) remains to be fully elucidated. This study aimed to investigate the oncogenic function of PRMT1 and assess the therapeutic efficacy of a selective PRMT1 inhibitor, C7280948, in CLL. Elevated expression of PRMT1 was observed in CLL cells and was associated with unfavorable prognosis. Additionally, in vitro and in vivo experiments demonstrated that treatment with C7280948 effectively inhibited tumor growth in CLL. Quantitative proteomics and co-immunoprecipitation analyses revealed an interaction between PRMT1 and MAST1, which was found to facilitate CLL progression. PRMT1 inhibition decreased the asymmetric dimethylarginine of MAST1 at R806 and downregulated the activation of the MAPK pathway by affecting the phosphorylation of MEK1 and ERK
Potentiating BSEP-mediated bile acid efflux reverses first-line tyrosine kinase inhibitor resistance in hepatocellular carcinoma.
Tyrosine kinase inhibitor (TKI) resistance limits therapy for hepatocellular carcinoma (HCC). Integrating RNA-seq and public cohort data, we found consistent downregulation of the bile salt export pump (BSEP/ABCB11) in TKI-resistant HCC associated with poorer prognosis and reduced clinical response. Functional in vitro and xenograft studies, using BSEP overexpression/knockdown and TKI-resistant cell lines plus targeted metabolomics, showed BSEP expression deficiency leads to intracellular accumulation of primary conjugated bile acids (BAs)-especially glycocholic acid (GCA)-which activates EGFR signaling and drives resistance; restoring BSEP enhances BA efflux and resensitizes cells and tumors to TKIs. Mechanistic assays revealed that ursodeoxycholic acid (UDCA) upregulated BSEP and reversed resistance via an FXR-independent mechanism: UDCA directly binds cortactin (CTTN), reduces its PRMT1-dependent mono-methylation, and promotes CTTN degradation via chaperone-mediated autophagy, there
Discovery of the First-in-Class Protein Arginine Methyltransferase 1 PROTAC Degrader.
Protein arginine methyltransferase 1 (PRMT1) plays a critical role in cancer, yet current PRMT1 modulators lack selectivity and rely on enzymatic inhibition. Here, we developed first-in-class PRMT1-targeting PROTAC degrader compound 4, designed based on the pharmacophore of our previously developed PRMT1 inhibitor. Compound 4 potently induces PRMT1 degradation in a concentration-, time-, and proteasome-dependent manner and exhibits high selectivity, with no detectable degradation of other common CRBN substrates and other type I PRMTs. It also effectively inhibited the growth of multiple cancer cell lines and exhibited a favorable pharmacokinetic profile. Molecular modeling suggests that the unique conformation of the PRMT1 dimerization arm promotes productive ternary complex formation with CRBN, providing a structural basis for selective PRMT1 degradation. Overall, this study demonstrates that compound 4 is a first-in-class PRMT1-targeting PROTAC degrader and highlights its value as a
Targeting PRMTs Creates Vulnerability of DNA Double-Stand Break Repair Pathways, and Potentiates Chemotherapy Efficacy in TNBC.
Patients with triple-negative breast cancer (ER-, PR-, and HER2-) are routinely treated with chemotherapies that induce DNA damage. However, around 30% of patients display resistance, owing largely to increased DNA repair mechanisms, upregulated to allow cancer cells to escape such therapies. PRMT1 and PRMT5, the two main protein arginine methyltransferases, are involved in several biological pathways, including DNA repair signaling, where they contribute to ensuring DNA integrity. We then speculated that targeting their enzymatic activity may sensitize TNBC cells to chemotherapeutic agents inducing DNA double-strand breaks. Here, we showed that PRMT1 and PRMT5 are recruited to DNA double-strand breaks upon doxorubicin or carboplatin treatment, two chemotherapies currently used to treat TNBC patients, and are preferentially involved in the homologous recombination pathway. By combining PRMT inhibitors with doxorubicin or carboplatin, we increased DNA double-strand breaks and impaired T
Arginine methylation-dependent stabilization of SUV39H1 promotes breast cancer growth.
Suppressors of variegation 3-9 homolog 1 (SUV39H1), the enzyme responsible for establishing histone H3 lysine 9 trimethylation (H3K9me3) marks in heterochromatin, is frequently dysregulated in cancers. However, the mechanisms underlying SUV39H1 dysregulation in breast cancer remain largely unclear. Here, we report that protein arginine methyltransferase 1 (PRMT1) directly interacts with SUV39H1 and dimethylates it at arginine 378 (R378). PKC signaling-mediated phosphorylation of SUV39H1 at S391 enhances this interaction, thereby promoting its methylation. Notably, PRMT1 binds to SUV39H1 with higher affinity and binding free energy than MDM2, causing a structural clash that blocks MDM2-mediated ubiquitination of SUV39H1. Moreover, methylated SUV39H1 exhibits enhanced H3K9me3 methyltransferase activity and promotes tumor cell growth. A SUV39H1-derived peptide (TAT-SUV-peptide) disrupts the interaction between PRMT1 and SUV39H1, thereby reducing SUV39H1 methylation. Administration of TAT-
Demonstrates potential therapeutic applications of PRMT1-rich exosomes, suggesting potential mechanisms for protein modification therapy.
1. Tissue Cell. 2026 Jun;100:103348. doi: 10.1016/j.tice.2026.103348. Epub 2026 Jan 24. PRMT1-rich exosomes derived from M2 macrophages as novel therapeutics for enhancing fracture healing. Hong...
Uses C. elegans model to profile PRMT-1 substrates, providing mechanistic insights into protein arginine methylation.
1. bioRxiv [Preprint]. 2026 Feb 16:2026.02.13.705869. doi: 10.64898/2026.02.13.705869. LC-MS profiling of prmt-1 and prmt-5 knockout C. elegans reveals PRMT-1 substrates and global proteome...
Protein arginine methyltransferases in cancer: mechanisms, functions, and therapeutic opportunities.
Evidence against (5)
Metformin suppresses gastric cancer progression by disrupting the STAT1-PRMT1 axis.
Gastric cancer (GC) is a common form of cancer and the leading cause of cancer-related deaths worldwide. Chemotherapy is the primary treatment for patients with unresectable or partially resectable GC. However, its adverse effects and chemoresistance greatly restrict its applicability and efficacy. Although HER2-targeted therapy and immunotherapy have been successfully used for GC treatment, their beneficial population is limited. To expand the range of cancer treatments, drug repurposing has emerged as a promising strategy. In this study, we evaluated the potential of Metformin, an oral anti-hyperglycemic agent, to suppress GC progression both in vivo and in vitro. Functional investigations showed that Metformin significantly inhibits GC proliferation and migration. Furthermore, we discovered that Metformin bound and disrupted STAT1 phosphorylation, inhibiting PRMT1 expression and consequently GC progression. In conclusion, our study not only provides further evidence for the anti-GC
Trans-Omic Analysis Identifies the 'PRMT1-STAT3-Integrin αVβ6 Axis' as a Novel Therapeutic Target in Tacrolimus-Induced Chronic Nephrotoxicity.
Tacrolimus-induced chronic nephrotoxicity (TACN) represents a major barrier to long-term graft survival in kidney transplantation, yet its molecular pathogenesis remains incompletely understood. We have previously reported metabolic abnormalities, including carnitine deficiency, nicotinamide adenine dinucleotide depletion, and elevated asymmetric dimethyl arginine (ADMA), in TACN. To identify upstream regulators associated with these metabolic disturbances, we conducted a comprehensive trans-omic analysis, integrating transcriptomics and proteomics of kidney tissues from male ICR mice with TACN (n = 5/group). Differentially expressed genes and proteins were subjected to functional enrichment and transcription factor binding motif analyses, followed by upstream master regulator identification using the Genome Enhancer platform. A total of 785 genes and 2472 proteins were differentially expressed, with partially discordant regulation between transcriptomic and proteomic profiles, undersc
Overexpression of PRMT1 promotes tau hyperphosphorylation and accelerates neurodegeneration in Alzheimer disease mouse models.
The formation of amyloid-like fibrils is a central problem in biophysical chemistry and medicine. Fibril formation and their deposition in various tissues and organs are associated with many human diseases. Searching for molecules able to prevent the formation of fibrils is, therefore, necessary. In this work, we examined the potential of a cocrystal (SS3) of 3-((4-(3-isocyanobenzyl) piperazine-1-yl) methy) benzonitrile with 5-hydroxy isophthalic acid, to prevent fibrillation of human serum albumin. We found that the cocrystal strongly bound to human serum albumin (HSA) with association constant (Ka) of 5.8 ± 0.7 × 105 M-1. The SS3 binding was found to cause small alterations in both secondary and tertiary structure of the protein. Transmission electron microscopy showed that the cocrystal completely prevented the formation of worm-like protofibrils by HSA at SS3/HSA molar ratio of 1:1. The molecule was found to prevent the aggregation in a concentration dependent manner. It was also o
PRMT1 inhibition paradoxically improves cognitive function and reduces neuroinflammation in aged mice through modulation of microglial activation.
Intussusception is a relatively common disease in pediatric age but it is uncommon in adults. We report a case of a 49-year-old male who presented with an acute jejunojejunal intussusception revealed by abdominal pain and vomiting. He underwent an en bloc resection, and pathological findings concluded to a metastasis of a pulmonary combined small cell carcinoma and adenocarcinoma. A subsequent CT scan revealed the primitive mass of the right lung with no evidence of secondary localization. The biopsy was difficult to perform. The patient underwent a pneumonectomy with lymph node dissection confirming the same diagnosis. He made a good recovery from the surgery, and a postoperative chemotherapy was administrated, and he is in remission until this date.
Excessive arginine methylation by PRMT1 disrupts synaptic plasticity and contributes to excitotoxicity in hippocampal neurons.
Quantum dots (QDs) have attracted much attention over the past decades due to their outstanding properties. However, obtaining QDs with excellent photoluminescence and quantum yields (QYs) from their aqueous synthesis is still a big concern. We herein present a green and facile synthesis of AgInS (AIS) QDs and AgInS-ZnS (AIS-ZnS) core-shell QDs using a combination of two capping agents (glutathione and sodium citrate). The temporal evolution of the optical properties is investigated by varying the reaction time and pH of the solution. The results show that the fluorescence intensity of the QDs increases as the reaction time increase, while the emission position blue-shift as the pH of the solution increase. An outstanding photoluminescence quantum yield (PLQY) of 90% is obtained at optimized synthetic conditions. The Fourier transform Infrared studies confirm efficient passivation of the QDs by the capping agents. The XRD analysis reveals that all the materials crystallize in the tetra