HNRNPA3 Gene

HNRNPA3 — Heterogeneous Nuclear Ribonucleoprotein A3

Overview

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](/diseases/neurodegeneration) research due to its involvement in [amyotrophic lateral sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis) and [frontotemporal dementia (FTD)](/diseases/frontotemporal-dementia), particularly in the context of [C9orf72 hexanucleotide repeat expansions](/genes/c9orf72). 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 — Heterogeneous Nuclear Ribonucleoprotein A3

Overview

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](/diseases/neurodegeneration) research due to its involvement in [amyotrophic lateral sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis) and [frontotemporal dementia (FTD)](/diseases/frontotemporal-dementia), particularly in the context of [C9orf72 hexanucleotide repeat expansions](/genes/c9orf72). 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.

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0; text-align:center;">HNRNPA3</th></tr>
<tr><td><b>Gene Symbol</b></td><td>HNRNPA3</td></tr>
<tr><td><b>Full Name</b></td><td>Heterogeneous Nuclear Ribonucleoprotein A3</td></tr>
<tr><td><b>Aliases</b></td><td>HNRPA3, H3, FUBP2</td></tr>
<tr><td><b>Chromosomal Location</b></td><td>10q12</td></tr>
<tr><td><b>NCBI Gene ID</b></td><td>10136</td></tr>
<tr><td><b>OMIM ID</b></td><td>605017</td></tr>
<tr><td><b>Ensembl ID</b></td><td>ENSG00000169020</td></tr>
<tr><td><b>UniProt ID</b></td><td>P51991</td></tr>
<tr><td><b>Protein Length</b></td><td>378 amino acids</td></tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
</div>

Normal Function

Protein Structure

HNRNPA3 belongs to the hnRNP A/B family, characterized by:

RNA Binding Specificity

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

Cellular Functions

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 |

Expression Pattern

HNRNPA3 is expressed in:

• Neurons (high expression in brain)
• Glial cells
• Most tissues (ubiquitous)

• Nucleus: Predominantly nuclear
• Cytoplasm: Shuttles between compartments
• Stress granules: Transient localization

Role in ALS and FTD

C9orf72 Connection

HNRNPA3 has a particularly important relationship with C9orf72:

Hexanucleotide Repeat Expansion

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

Sequestration in DPR Aggregates

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

HNRNPA3 Mutations

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

Stress Granule Involvement

HNRNPA3 is a stress granule component:

Stress granules are membrane-less organelles that form under stress conditions. In neurodegeneration, persistent stress granules contribute to pathology.

Molecular Mechanisms in Neurodegeneration

RNA Toxicity

Gain-of-Function Mechanisms

Expanded C9orf72 repeats cause RNA toxicity through:

HNRNPA3 Dysregulation

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

Protein Aggregation

HNRNPA3 interacts with other aggregation-prone proteins:

TDP-43 Pathology

• HNRNPA3 colocalizes with [TDP-43](/mechanisms/tdp-43-proteinopathy) inclusions
• Both are recruited to stress granules
• TDP-43 pathology is hallmark of ALS/FTD

FUS Pathology

• Related hnRNP family member
• Shared stress granule localization
• Similar aggregation mechanisms

Nuclear-Cytoplasmic Transport Defects

HNRNPA3 shuttling is affected in disease:

• Nuclear import disruption: Reduced nuclear localization
• Cytoplasmic accumulation: Enhanced cytoplasmic presence
• Transport defects: Impaired nucleocytoplasmic trafficking

Disease Associations

Amyotrophic Lateral Sclerosis (ALS)

| 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 |

Frontotemporal Dementia (FTD)

• TDP-43 pathology: HNRNPA3 in inclusions
• Language variants: Specific splicing alterations
• Behavioral variant: RNA processing deficits

Other Neurodegenerative Diseases

Alzheimer's Disease

• Altered RNA processing in AD
• Stress granule abnormalities
• Potential for therapeutic targeting

Parkinson's Disease

• RNA metabolism defects
• Stress response alterations
• Protein homeostasis disruption

Research Models

Cell Culture Models

• Neuronal cell lines: SH-SY5Y, NSC-34
• Primary neurons: Cortical, motor neurons
• iPSC-derived: Patient-specific neurons

• C9orf72 repeat RNA induces HNRNPA3 mislocalization
• DPR expression alters HNRNPA3 distribution
• Loss of HNRNPA3 exacerbates toxicity

Animal Models

• Drosophila: Homologous hnRNP studies
• Zebrafish: Morpholino knockdowns
• Mice: Transgenic models

• HNRNPA3 knockdown worsens C9orf72 phenotype
• Overexpression is protective in some contexts
• Stress granule dynamics altered

Molecular Studies

• RNA-seq: Transcriptomic changes
• CLIP-seq: RNA binding targets
• Proteomics: Interaction networks

Therapeutic Implications

Targeting RNA Metabolism

Modulating HNRNPA3 function represents a therapeutic strategy:

RNA-Targeting Approaches

Stress Granule Modulation

• Granule disassembly: Promote clearance
• Assembly inhibitors: Prevent formation
• Function preservation: Maintain protective functions

Biomarker Potential

HNRNPA3 as a biomarker:

| Marker Type | Application |
|-------------|-------------|
| Genetic | Mutation screening |
| Expression | Disease diagnosis |
| Localization | Pathology detection |
| Fluid | Disease monitoring |

Interaction Network

Core Interactors

| 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 |

RNA Targets

• C9orf72 expanded repeat RNA
• GU-rich sequences
• Pre-mRNA splicing substrates
• Neuronal transcript isoforms

Signaling Pathways

• Stress response: p-eIF2α pathway
• Translation: mTOR signaling
• Cell death: Apoptosis signaling

Cross-Linking to Related Topics

Mechanisms

• [RNA Metabolism in Neurodegeneration](/mechanisms/rna-metabolism) — RNA processing defects
• [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy) — TDP-43 pathology
• [Stress Granules in Disease](/mechanisms/stress-granules-neurodegeneration) — Granule dynamics

Related Genes

• [C9orf72](/genes/c9orf72) — Primary ALS-FTD gene
• [TARDBP](/genes/tardbp) — TDP-43 encoding gene
• [FUS](/genes/fus) — FUS protein gene
• [TDP-43](/mechanisms/tdp-43-proteinopathy) — Related RBP

Related Proteins

• [hnRNP A1](/proteins/hnrnp-a1) — Related family member
• [TDP-43 Protein](/proteins/tdp-43-protein) — Aggregate component

Diseases

• [ALS](/diseases/amyotrophic-lateral-sclerosis) — Primary disease association
• [FTD](/diseases/frontotemporal-dementia) — Spectrum disease
• [ALS-FTD Spectrum](/diseases/als-ftd-spectrum) — Clinical overlap

Research Directions

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

Emerging Areas

Future Questions

• Can HNRNPA3 modulation slow disease progression?
• What determines neuronal vulnerability?
• Are there protective vs toxic HNRNPA3 species?

Key Publications

See Also

• [TDP-43](/mechanisms/tdp-43-proteinopathy)
• [ALS](/diseases/amyotrophic-lateral-sclerosis)
• [FTD](/diseases/frontotemporal-dementia)
• [RNA Granules](/mechanisms/rna-granules-neurodegeneration)
• [Stress Response in Neurodegeneration](/mechanisms/stress-response-neurodegeneration)

External Links

• [PubMed - HNRNPA3](https://pubmed.ncbi.nlm.nih.gov/10136/)
• [NCBI Gene: HNRNPA3](https://www.ncbi.nlm.nih.gov/gene/10136)
• [UniProt: HNRNPA3](https://www.uniprot.org/uniprotkb/P51991)
• [GeneCards: HNRNPA3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=HNRNPA3)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References