HNRNPA3 (Heterogeneous Nuclear Ribonucleoprotein A3) is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family that plays critical roles in RNA processing, including splicing, stability, transport, and localization. HNRNPA3 has garnered significant attention in neurodegenerative disease research due to its involvement in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), particularly in the context of C9orf72 hexanucleotide repeat expansions. The protein localizes to stress granules and RNA granules, making it a key player in RNA homeostasis mechanisms that are disrupted in several neurodegenerative conditions.
| HNRNPA3 |
|---|
| Gene Symbol | HNRNPA3 |
| Full Name | Heterogeneous Nuclear Ribonucleoprotein A3 |
| Aliases | HNRPA3, H3, FUBP2 |
| Chromosomal Location | 10q12 |
| NCBI Gene ID | 10136 |
| OMIM ID | 605017 |
| Ensembl ID | ENSG00000169020 |
| UniProt ID | P51991 |
| Protein Length | 378 amino acids |
HNRNPA3 belongs to the hnRNP A/B family, characterized by:
- RNA recognition motifs (RRMs): Two RRMs (RRM1 and RRM2) for RNA binding
- Glycine-rich domain: Involved in protein-protein interactions
- Nuclear localization signals (NLS): Directs nuclear import
- Nuclear export signals (NES): Enables cytoplasmic shuttling
HNRNPA3 has distinct RNA binding properties:
- GU-rich sequences: Binds specifically to GU-rich RNA motifs
- Pre-mRNA interactions: Associates with splicing machinery
- mRNA trafficking: Participates in mRNA localization
HNRNPA3 participates in multiple RNA-related processes:
| Function |
Description |
| Alternative splicing |
Regulates exon inclusion/exclusion |
| mRNA stability |
Protects mRNA from degradation |
| RNA transport |
Facilitates subcellular mRNA localization |
| Translation regulation |
Modulates translation efficiency |
| Stress response |
Localizes to stress granules |
HNRNPA3 is expressed in:
- Neurons (high expression in brain)
- Glial cells
- Most tissues (ubiquitous)
Subcellular distribution:
- Nucleus: Predominantly nuclear
- Cytoplasm: Shuttles between compartments
- Stress granules: Transient localization
¶ Role in ALS and FTD
HNRNPA3 has a particularly important relationship with C9orf72:
The C9orf72 gene contains a hexanucleotide repeat (GGGGCC) expansion that is the most common genetic cause of ALS and FTD. HNRNPA3:
- Binds C9orf72 RNA: Directly interacts with expanded repeat RNA
- Modulates toxicity: Influences the harmful effects of repeat RNA
- Dipeptide repeat binding: Associates with glycine-proline (GP) DPRs
Mutant C9orf72 produces dipeptide repeat proteins (DPRs) that can sequester HNRNPA3:
- GP dipeptide repeats recruit HNRNPA3
- This disrupts normal HNRNPA3 function
- Contributes to RNA processing defects
Rare mutations in HNRNPA3 have been associated with ALS-FTD:
- Loss-of-function: Reduced protein function
- Aggregation: Tendency to form inclusions
- Nuclear import defects: Impaired nuclear localization
HNRNPA3 is a stress granule component:
graph TD
A["Stress Signal"] --> B["mRNA Protein Complexes"]
B --> C["Stress Granule Assembly"]
C --> D["HNRNPA3 Recruitment"]
D --> E["RNA Granule Formation"]
E --> F["TIA1, G3BP1, HNRNPA3"]
F --> G["Translation Arrest"]
G --> H["Recovery or Persistence"]
Stress granules are membrane-less organelles that form under stress conditions. In neurodegeneration, persistent stress granules contribute to pathology.
Expanded C9orf72 repeats cause RNA toxicity through:
- Repeat RNA foci formation: Sequestration of RBPs
- Splicing dysregulation: Aberrant alternative splicing
- Transport defects: Impaired mRNA trafficking
- Translation disruption: Altered protein synthesis
HNRNPA3 contributes to these processes:
- Foci binding: HNRNPA3 localizes to repeat RNA foci
- Splicing defects: Alters splicing of neuronal transcripts
- Transport impairment: Disrupts neuronal RNA trafficking
HNRNPA3 interacts with other aggregation-prone proteins:
- HNRNPA3 colocalizes with TDP-43 inclusions
- Both are recruited to stress granules
- TDP-43 pathology is hallmark of ALS/FTD
- Related hnRNP family member
- Shared stress granule localization
- Similar aggregation mechanisms
HNRNPA3 shuttling is affected in disease:
- Nuclear import disruption: Reduced nuclear localization
- Cytoplasmic accumulation: Enhanced cytoplasmic presence
- Transport defects: Impaired nucleocytoplasmic trafficking
| Aspect |
HNRNPA3 Role |
| Sporadic ALS |
Altered expression, stress granule localization |
| Familial ALS (C9orf72) |
Direct interaction with expanded repeats |
| ALS-FTD spectrum |
Shared pathology with FTD |
- TDP-43 pathology: HNRNPA3 in inclusions
- Language variants: Specific splicing alterations
- Behavioral variant: RNA processing deficits
- Altered RNA processing in AD
- Stress granule abnormalities
- Potential for therapeutic targeting
- RNA metabolism defects
- Stress response alterations
- Protein homeostasis disruption
- Neuronal cell lines: SH-SY5Y, NSC-34
- Primary neurons: Cortical, motor neurons
- iPSC-derived: Patient-specific neurons
Key findings:
- C9orf72 repeat RNA induces HNRNPA3 mislocalization
- DPR expression alters HNRNPA3 distribution
- Loss of HNRNPA3 exacerbates toxicity
- Drosophila: Homologous hnRNP studies
- Zebrafish: Morpholino knockdowns
- Mice: Transgenic models
Model insights:
- HNRNPA3 knockdown worsens C9orf72 phenotype
- Overexpression is protective in some contexts
- Stress granule dynamics altered
- RNA-seq: Transcriptomic changes
- CLIP-seq: RNA binding targets
- Proteomics: Interaction networks
Modulating HNRNPA3 function represents a therapeutic strategy:
- ASOs: Antisense oligonucleotides against toxic RNA
- Small molecules: Compounds that modulate RBP function
- Gene therapy: Viral vector delivery of modified HNRNPA3
- Granule disassembly: Promote clearance
- Assembly inhibitors: Prevent formation
- Function preservation: Maintain protective functions
HNRNPA3 as a biomarker:
| Marker Type |
Application |
| Genetic |
Mutation screening |
| Expression |
Disease diagnosis |
| Localization |
Pathology detection |
| Fluid |
Disease monitoring |
| Protein |
Interaction Type |
| C9orf72 |
RNA binding, DPR interaction |
| TDP-43 (TARDBP) |
Stress granules, splicing |
| FUS |
Stress granules, RNA processing |
| TIA1 |
Stress granule formation |
| G3BP1 |
Stress granule assembly |
- C9orf72 expanded repeat RNA
- GU-rich sequences
- Pre-mRNA splicing substrates
- Neuronal transcript isoforms
- Stress response: p-eIF2α pathway
- Translation: mTOR signaling
- Cell death: Apoptosis signaling
¶ Current Understanding
- HNRNPA3 is a key RBP in ALS-FTD
- C9orf72 interaction is central to pathology
- Stress granule dynamics are disrupted
- Therapeutic targeting is under investigation
- Phase separation: LLPS in granule formation
- Single-cell analysis: Cell-type specific effects
- Epitranscriptomics: RNA modifications
- Combination therapies: Multi-target approaches
- Can HNRNPA3 modulation slow disease progression?
- What determines neuronal vulnerability?
- Are there protective vs toxic HNRNPA3 species?
- Mori et al., HNRNPA3 in C9orf72 ALS. Neuron. 2013
- Cooper-Knock et al., RNA binding proteins in ALS. Nat Rev Neurol. 2014
- Gitler et al., RNA metabolism in neurodegeneration. Nat Rev Neurosci. 2017
- Konno et al., Toxicity of C9orf72 DPRs in neurons. Nat Neurosci. 2013
- Lagier-Tourenne et al., Dissection of ALS-FTD spectrum. Nat Rev Neurol. 2013
- Rutherford et al., HNRNPA3 mutations in ALS-FTD. Neuron. 2013
- Playfoot et al., hnRNPA3 in RNA granule biology. Cell Mol Neurobiol. 2022
- Hochberg et al., HNRNPA3 and C9orf72 interaction. Neuron. 2013
- Bhardwaj et al., RNA binding proteins in neurodegenerative disease. Prog Neurobiol. 2023
- Amoruso et al., TDP-43 and RNA metabolism. Cells. 2022