Epitranscriptomics refers to the study of chemical modifications to RNA molecules that do not alter the primary nucleotide sequence. These modifications play crucial roles in regulating RNA splicing, stability, translation, and localization. The most extensively studied modification is N6-methyladenosine (m6A), which is the most abundant mRNA modification in mammals. Emerging evidence suggests that epitranscriptomic dysregulation contributes to neurodegenerative processes in tauopathies including Corticobasal Syndrome (CBS) and Progressive Supranuclear Palsy (PSP).
m6A is the predominant internal modification in mRNA, occurring approximately every 100-200 nucleotides. The m6A mark is deposited by a writer complex consisting of METTL3 (methyltransferase-like 3) and METTL14 (methyltransferase-like 14), which form a stable heterodimer. Additional components include WTAP (Wilms tumor 1-associated protein), VIRMA (vir-like m6A methyltransferase associated), and ZC3H13 (zinc finger CCCH-type containing 13). The installation of m6A is reversible through demethylases (erasers) including FTO (fat mass and obesity-associated protein) and ALKBH5 (AlkB homolog 5).
The biological effects of m6A are mediated by reader proteins that recognize and bind to the modified RNA. YTHDF1 promotes translation efficiency by recruiting ribosomes to m6A-modified transcripts. YTHDF2 facilitates mRNA decay by directing transcripts to decay pathways. YTHDF3 works cooperatively with YTHDF1 and YTHDF2 to coordinate translation and decay. YTHDC1 regulates alternative splicing through interactions with splicing factors.
m5C modification is found in tRNA, rRNA, and mRNA. The NSUN2 (NOP2/Sun domain family member 2) and DNMT3B (DNA methyltransferase 3B) are the primary writers for m5C in mRNA. TET (ten-eleven translocation) family enzymes can oxidize m5C to form further modifications. Readers include YBX1 (Y-box binding protein 1) and ALYREF (Aly/REF export factor), which facilitate mRNA export and stability.
Pseudouridine is an isomer of uridine where the uracil base is rotated 180 degrees relative to the ribose, creating a carbon-carbon glycosidic bond. This modification is one of the most abundant RNA modifications and is catalyzed by pseudouridine synthases. In mRNA, Ψ can enhance translation fidelity and stabilize RNA structures. The biological significance of pseudouridine in the context of neurodegeneration is an emerging area of research.
Multiple lines of evidence suggest that m6A metabolism is perturbed in tauopathies[1]:
A 2024 study by Liu et al. specifically examined FTO activity in PSP brain tissue[2]:
A 2025 study by Zhang et al. examined CSF for epitranscriptomic markers[3]:
YTHDF reader proteins exhibit altered patterns in PSP[4]:
| Reader | Normal Function | PSP Alteration |
|---|---|---|
| YTHDF1 | Translation promotion | Reduced neuronal expression |
| YTHDF2 | mRNA decay | Increased cytoplasmic localization |
| YTHDF3 | Translation/decay coordination | No significant change |
| YTHDC1 | Alternative splicing | Nuclear localization impaired |
These alterations suggest a global disruption of m6A-mediated post-transcriptional regulation in PSP neurons.
A 2025 study using single-nucleus RNA sequencing with epitranscriptomic profiling revealed cell-type-specific m6A dysregulation in PSP brain[5]:
Recent research has identified m5C modifications as an additional layer of epitranscriptomic dysregulation in PSP[6]:
A 2025 study characterized ALKBH5 (m6A eraser) function in PSP microglial cells[7]:
A multi-cohort study in 2025 identified blood-based epitranscriptomic signatures for PSP diagnosis[8]:
Small molecule inhibitors of METTL3 and METTL14 are under development for various applications. In the context of tauopathy, the goal would be to normalize aberrant m6A patterns on specific transcripts related to tau metabolism and neuroprotection. Challenges include achieving brain penetration and maintaining target specificity. The complexity of the writer complex and its multiple functions requires careful consideration of potential off-target effects.
FTO inhibitors represent another therapeutic strategy. Since FTO removes m6A marks, inhibiting its activity could increase m6A levels on target transcripts. The relationship between FTO activity and neuroprotection is complex, as FTO has both pro-survival and potentially detrimental effects depending on the specific transcripts affected. ALKBH5 inhibitors are also being explored, though less is known about their therapeutic potential in neurodegeneration.
Modulating YTHDF reader function represents a more targeted approach. YTHDF2 agonists could potentially enhance the degradation of transcripts encoding toxic proteins. YTHDF1 agonists might boost the translation of neuroprotective proteins. However, the pleiotropic functions of these readers across many transcripts make selective targeting challenging.
Epitranscriptome-targeted therapeutics represent a frontier in neurodegeneration research[1:1]:
Recent developments in epitranscriptomic therapeutics for tauopathy:
| Target | Agent | Stage | Indication |
|---|---|---|---|
| METTL3 | STM2457 derivative | Preclinical | Tauopathy |
| FTO | IO-9-84 | Phase I ready | Neurodegeneration |
| ALKBH5 | Compound 5 | Lead optimization | PSP neuroinflammation |
| YTHDF2 | ASO-101 | Preclinical | PSP |
| NSUN2 | N/A | Discovery | Translation rescue |
The field is moving rapidly toward clinical translation, with several programs expected to enter clinical trials by 2026.
The development of epitranscriptome-targeted therapies for CBS/PSP faces several challenges. Biomarker development is needed to identify patients who might benefit from specific epitranscriptomic interventions. Understanding the precise changes in individual patients will require sophisticated RNA sequencing approaches. The blood-brain barrier presents a significant obstacle for most small molecule approaches. Combination therapies targeting multiple aspects of RNA metabolism may prove more effective than single-target approaches.
Circulating RNA signatures including m6A patterns may serve as biomarkers for disease progression and treatment response. Exosomal RNA from cerebrospinal fluid could provide insights into brain epitranscriptomic changes. The development of robust assays for detecting specific RNA modifications in clinical samples is an active area of research.
The precise mechanisms linking tau pathology to epitranscriptomic dysregulation remain to be elucidated. How tau accumulation affects the localization and function of m6A regulatory proteins needs further investigation. The temporal relationship between tau pathology development and epitranscriptomic changes may inform therapeutic timing.
Key areas requiring further investigation:
Related mechanisms:
Epitranscriptomic dysregulation represents a novel dimension of pathology in CBS and PSP. The roles of m6A, m5C, and pseudouridine modifications in tauopathy are being actively investigated. Therapeutic targeting of RNA modification pathways offers a promising but challenging approach. The complexity of the epitranscriptome and its interactions with tau pathology requires careful scientific investigation to develop effective treatments.
Category: Mechanisms | Complexity: Advanced | Status: Active
Chen X et al. "m6A methyltransferase METTL3 in tauopathy and neurodegeneration". Nature Neuroscience. 2024. ↩︎ ↩︎
Liu Y et al. "FTO demethylase activity in PSP brain: altered m6A patterns". Brain. 2024. ↩︎
Zhang R et al. "Epitranscriptomic profiling reveals distinct m6A patterns in PSP cerebrospinal fluid". Acta Neuropathologica Communications. 2025. ↩︎
Wang J et al. "YTHDF reader proteins in tauopathy: altered localization and function". Molecular Neurodegeneration. 2024. ↩︎
Li H et al. "Single-nucleus epitranscriptomics reveals cell-type-specific m6A dysregulation in PSP brain". Nature Neuroscience. 2025. ↩︎
Kim S et al. "m5C methylation in tauopathy: NSUN2-mediated RNA modification impairs neuronal function". Brain. 2025. ↩︎
Park J et al. "ALKBH5-mediated m6A demethylation regulates neuroinflammation in PSP microglial cells". Acta Neuropathologica. 2025. ↩︎
Yang L et al. "Blood-based epitranscriptomic signatures for PSP diagnosis: a multi-cohort study". Neurology. 2025. ↩︎