RNA metabolism dysfunction represents an emerging area of research in corticobasal syndrome (CBS) and related 4-repeat (4R) tauopathies. While classically characterized by tau protein pathology, growing evidence indicates that RNA binding protein dysregulation, splicing abnormalities, and translational defects contribute significantly to disease pathogenesis. This mechanism page synthesizes current knowledge about RNA metabolism alterations in CBS, with particular focus on RNA binding proteins (RBPs), splicing defects, and mRNA translation abnormalities.
The relationship between tau pathology and RNA metabolism dysfunction creates a pathogenic feed-forward loop: tau aggregates can sequester RNA binding proteins, impairing their normal function, while RNA metabolism defects can promote aberrant tau phosphorylation and aggregation[@li2025][@chen2024]. Understanding these interactions provides novel therapeutic targets for CBS treatment.
TDP-43, encoded by the [TARDBP](/genes/tardbp) gene, is a highly conserved RNA/DNA binding protein that plays critical roles in RNA splicing, transport, and stability. While TDP-43 pathology is most famously associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), significant TDP-43 dysfunction occurs in CBS[@murakami2025].
RNA metabolism dysfunction represents an emerging area of research in corticobasal syndrome (CBS) and related 4-repeat (4R) tauopathies. While classically characterized by tau protein pathology, growing evidence indicates that RNA binding protein dysregulation, splicing abnormalities, and translational defects contribute significantly to disease pathogenesis. This mechanism page synthesizes current knowledge about RNA metabolism alterations in CBS, with particular focus on RNA binding proteins (RBPs), splicing defects, and mRNA translation abnormalities.
The relationship between tau pathology and RNA metabolism dysfunction creates a pathogenic feed-forward loop: tau aggregates can sequester RNA binding proteins, impairing their normal function, while RNA metabolism defects can promote aberrant tau phosphorylation and aggregation[@li2025][@chen2024]. Understanding these interactions provides novel therapeutic targets for CBS treatment.
TDP-43, encoded by the [TARDBP](/genes/tardbp) gene, is a highly conserved RNA/DNA binding protein that plays critical roles in RNA splicing, transport, and stability. While TDP-43 pathology is most famously associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), significant TDP-43 dysfunction occurs in CBS[@murakami2025].
TDP-43 pathology is present in approximately 30-50% of CBS cases, often as co-pathology with 4R tau aggregates. The distribution includes:
Beyond visible protein aggregates, TDP-43 function is impaired in CBS through several mechanisms:
FUS, encoded by the [FUS](/genes/fus) gene, is another RNA binding protein implicated in CBS pathogenesis. Like TDP-43, FUS is associated with ALS/FTD spectrum disorders but shows distinct patterns of involvement in CBS[@neumann2024].
FUS dysfunction in CBS affects multiple RNA processing pathways:
The hnRNP family of proteins, including [HNRNPA1](/genes/hnrnpa1), hnRNPA2/B1, and hnRNP A1, are essential for RNA processing. These proteins are increasingly recognized as important players in CBS pathogenesis[@biamonte2024].
hnRNPA1, encoded by the [HNRNPA1](/genes/hnrnpa1) gene, shows altered expression and localization in CBS:
RNA splicing dysregulation is a hallmark of CBS pathogenesis. Several splicing events are specifically altered:
The most critical splicing defect in 4R tauopathies involves exon 10 of the MAPT gene:
The balance between 3R and 4R tau isoforms is critical. In CBS, splicing regulatory proteins that control exon 10 inclusion are dysfunctional, leading to 4R tau overexpression["@andreadis2023"][@hernandez2024].
Several neuron-specific splicing events are disrupted in CBS:
| Splicing Event | Normal Function | CBS Dysfunction |
|---------------|------------------|------------------|
| NMDAR subunit splicing | Synaptic plasticity | Cognitive decline |
| Apoptotic gene splicing | Cell survival | Increased neuronal death |
| Cytoskeletal protein splicing | Axonal transport | Transport deficits |
Key splicing factors affected in CBS include:
Translation initiation and elongation are impaired in CBS through multiple mechanisms:
Stress-induced phosphorylation of eIF2α (encoded by EIF2S1) leads to global translation repression:
Ribosome stalling on defective mRNAs contributes to translation deficits:
Synaptic-localized translation is particularly affected in CBS:
For more on synaptic dysfunction in CBS, see [Synaptic Dysfunction in Corticobasal Syndrome](/mechanisms/cbs-synaptic-dysfunction).
Tau protein directly binds to RNA, and this interaction is altered in CBS:
In CBS, tau pathology sequesters RNA binding proteins:
The RNA metabolism-tau interaction provides novel therapeutic targets:
RNA metabolism dysfunction intersects with multiple other pathological mechanisms in CBS:
For details on how RNA metabolism affects protein clearance, see [Autophagy-Lysosomal Pathway Dysfunction in Corticobasal Syndrome](/mechanisms/autophagy-lysosomal-cbs).
RNA metabolism defects contribute to ER stress. See [CBS ER Stress and Unfolded Protein Response Mechanisms](/mechanisms/cbs-er-stress-unfolded-protein-response).
RNA binding protein pathology influences neuroinflammatory responses. See [Neuroinflammation in Corticobasal Syndrome](/mechanisms/cbs-neuroinflammation).
RNA metabolism markers in cerebrospinal fluid (CSF) and blood represent promising biomarkers:
Current therapeutic approaches include:
Recent single-nucleus RNA sequencing studies have revealed cell-type-specific RNA metabolism defects in CBS post-mortem brain tissue. Single-nucleus transcriptomics of CBS motor cortex and basal ganglia has identified:
N6-methyladenosine (m6A) RNA modifications, regulated by writers (METTL3, METTL14), erasers (FTO, ALKBH5), and readers (YTHDF1-3), are increasingly recognized in CBS:
Circular RNAs (circRNAs), generated by back-splicing of pre-mRNA, show CBS-specific alterations:
Long non-coding RNAs (lncRNAs) participate in CBS pathogenesis through chromatin remodeling and RNA processing regulation:
Specific microRNAs are altered in CBS CSF, serum, and brain tissue:
| microRNA | Change | Target | Functional Consequence |
|----------|--------|--------|----------------------|
| miR-9 | Upregulated | REST | Neuronal differentiation changes |
| miR-124 | Downregulated | PTBP1 | Splicing dysregulation |
| miR-132 | Downregulated | Gephyrin | Synaptic dysfunction |
| miR-146a | Upregulated | IRAK1 | Neuroinflammation |
| miR-155 | Upregulated | SOCS1 | Immune modulation |
snoRNAs, particularly those encoded in introns of host genes, show CBS-specific alterations:
Nuclear export of processed mRNA is impaired in CBS:
Ribosomal RNA processing is altered in CBS:
RNA metabolism dysfunction in CBS differs from other 4R tauopathies:
| Feature | CBS | PSP | CBD |
|---------|-----|-----|-----|
| TDP-43 pathology | 30-50% | 10-15% | 5-10% |
| FUS pathology | 15-25% | <5% | <5% |
| MAPT splicing defect | Primary | Primary | Primary |
| circRNA dysregulation | Severe | Moderate | Moderate |
| m6A modifications | Altered | Less studied | Less studied |
RNA metabolism dysfunction is a critical but underappreciated mechanism in CBS pathogenesis. The interplay between RNA binding protein pathology (TDP-43, FUS, hnRNPs), splicing abnormalities, and translation defects creates a self-perpetuating cycle of neurodegeneration. Recent advances in single-nucleus transcriptomics and epitranscriptomics have revealed cell-type-specific RNA metabolism defects that correlate with selective neuronal vulnerability in CBS[@wang2024][@kim2025]. Understanding these mechanisms provides crucial insights for developing disease-modifying therapies for CBS and related 4R tauopathies.