NONO Gene

NONO — Non-POU Domain Containing Octamer Binding

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">NONO</th></tr> [@birsa2019]
<tr><td><strong>Gene Symbol</strong></td><td>NONO</td></tr> [@pavlath2018]
<tr><td><strong>Full Name</strong></td><td>Non-POU Domain Containing Octamer Binding</td></tr> [@zhang2017]
<tr><td><strong>Chromosome</strong></td><td>Xq13.1</td></tr> [@amsterdam2020]
<tr><td><strong>NCBI Gene ID</strong></td><td>[4841](https://www.ncbi.nlm.nih.gov/gene/4841)</td></tr> [@dye2018]
<tr><td><strong>OMIM</strong></td><td>300084</td></tr> [@xiao2021]
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000147140</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q13435](https://www.uniprot.org/uniprot/Q13435)</td></tr>
<tr><td><strong>Protein Type</strong></td><td>RNA-binding protein, DBHS family</td></tr>
<tr><td><strong>Cellular Location</strong></td><td>Nuclear speckles, Paraspeckles, Nucleus</td></tr>
<tr><td><strong>Brain Expression</strong></td><td>Motor [neurons](/entities/neurons), Cortical neurons, [Hippocampus](/brain-regions/hippocampus)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">9 edges</a></td>
</tr>
</table>
</div>

Introduction

NONO — Non-POU Domain Containing Octamer Binding

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">NONO</th></tr> [@birsa2019]
<tr><td><strong>Gene Symbol</strong></td><td>NONO</td></tr> [@pavlath2018]
<tr><td><strong>Full Name</strong></td><td>Non-POU Domain Containing Octamer Binding</td></tr> [@zhang2017]
<tr><td><strong>Chromosome</strong></td><td>Xq13.1</td></tr> [@amsterdam2020]
<tr><td><strong>NCBI Gene ID</strong></td><td>[4841](https://www.ncbi.nlm.nih.gov/gene/4841)</td></tr> [@dye2018]
<tr><td><strong>OMIM</strong></td><td>300084</td></tr> [@xiao2021]
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000147140</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q13435](https://www.uniprot.org/uniprot/Q13435)</td></tr>
<tr><td><strong>Protein Type</strong></td><td>RNA-binding protein, DBHS family</td></tr>
<tr><td><strong>Cellular Location</strong></td><td>Nuclear speckles, Paraspeckles, Nucleus</td></tr>
<tr><td><strong>Brain Expression</strong></td><td>Motor [neurons](/entities/neurons), Cortical neurons, [Hippocampus](/brain-regions/hippocampus)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">9 edges</a></td>
</tr>
</table>
</div>

Introduction

NONO (Non-POU Domain Containing Octamer Binding) encodes a nuclear RNA-binding protein that belongs to the DBHS (Drosophila Behavior and Human Splicing) protein family. Like its paralog [SFPQ](/genes/sfpq), NONO plays critical roles in alternative splicing, transcriptional regulation, RNA processing, and DNA damage response. NONO forms heterodimeric complexes with SFPQ and PSPC1 to regulate gene expression at multiple levels. Mutations in NONO have been implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and X-linked intellectual disability, highlighting its essential role in neuronal function and survival.

Overview

NONO is an X-linked gene encoding a protein that is ubiquitously expressed with particularly high levels in the brain, especially in motor neurons, cortical neurons, and the hippocampus. The protein localizes to nuclear speckles and paraspeckles, which are subnuclear compartments involved in RNA processing and storage. NONO participates in diverse cellular functions including transcriptional regulation, RNA splicing, circadian rhythm maintenance, and DNA damage repair.

Pathogenic mutations in NONO cause neurodegeneration through disrupted RNA processing and impaired cellular stress responses. The discovery of NONO mutations in ALS and FTD has expanded understanding of how RNA metabolism defects contribute to these devastating diseases.

Protein Structure and Function

Domain Architecture

NONO contains several functional domains:

• N-terminal region: Involved in protein-protein interactions
• DBHS domain: Conserved region comprising two RNA recognition motifs (RRMs) and an HTH (helix-turn-helix) domain
• C-terminal region: Mediates multimerization and nuclear localization

Molecular Functions

NONO performs multiple critical cellular functions:

Protein Complexes

NONO forms several important complexes:

• SFPQ-NONO heterodimer: Primary functional complex for RNA processing
• PSPC1-NONO-SFPQ trimers: Extended DBHS complexes
• Nuclear receptor complexes: Interaction with steroid hormone receptors
• DNA repair complexes: Participation in the DNA damage response

Expression and Localization

Brain Expression Pattern

NONO exhibits high expression in the nervous system:

| Brain Region | Expression Level | Cell Types |
|--------------|-----------------|------------|
| Motor [Cortex](/brain-regions/cortex) | High | Upper motor neurons, Interneurons |
| Spinal Cord | Very High | Lower motor neurons |
| Hippocampus | High | CA1-CA3 pyramidal neurons |
| Frontal Cortex | High | Cortical pyramidal neurons |
| Hypothalamus | High | Suprachiasmatic nucleus (circadian) |
| Basal Ganglia | Moderate | Dopaminergic neurons |

Subcellular Localization

• Primary location: Nuclear speckles
• Paraspeckles: Induced by cellular stress
• Nucleoplasm: Diffuse distribution for transcriptional functions
• Cytoplasmic: Transient during stress granule formation

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis

NONO mutations are associated with familial amyotrophic lateral sclerosis (ALS):

• G400W mutation: Disrupts RNA processing function, leading to splicing defects
• G192S mutation: Impairs protein-protein interactions essential for RNA metabolism
• RNA splicing defects: Aberrant alternative splicing of transcripts critical for motor neuron survival
• Stress granule dysfunction: Altered stress response contributing to cellular vulnerability

Frontotemporal Dementia

NONO mutations also cause frontotemporal dementia (FTD):

• RNA metabolism dysregulation: Similar to ALS, disrupts normal RNA processing
• [TDP-43](/mechanisms/tdp-43-proteinopathy) interaction: Functional overlap with other ALS/FTD proteins
• Neuronal nuclear dysfunction: Nuclear speckle disruption and impaired nuclear functions

Intellectual Disability

X-linked intellectual disability is associated with NONO mutations:

• Developmental deficits: Impaired neuronal development due to RNA processing defects
• X-linked inheritance: Males affected, females may be carriers

Alzheimer's Disease

While less directly implicated, NONO dysfunction may contribute to Alzheimer disease through:

• Alternative splicing defects: Dysregulated splicing of [tau](/proteins/tau) and [APP](/entities/app-protein) transcripts
• DNA damage accumulation: Impaired DNA repair contributing to neuronal senescence
• Circadian rhythm disruption: Sleep disturbances common in AD

Pathogenic Mechanisms

RNA Splicing Dysregulation

NONO mutations lead to widespread changes in RNA processing:

Circadian Rhythm Disruption

NONO plays a critical role in circadian regulation:

• Clock gene regulation: Controls expression of circadian clock components
• Circadian output: Mediates rhythmic physiological functions
• Sleep-wake cycles: Dysregulation may contribute to neurodegeneration

DNA Damage Response

NONO participates in DNA repair:

• Double-strand break repair: Essential for genomic integrity
• Transcription-coupled repair: Links transcription to DNA repair
• Genomic instability: Defects contribute to neuronal dysfunction

Therapeutic Implications

NONO represents a therapeutic target for ALS and FTD:

RNA-Targeting Therapies

• Antisense oligonucleotides: Modulate NONO splicing or expression
• Splicing modulators: Restore normal RNA processing patterns
• RNA delivery: Viral vector-mediated gene delivery

Gene Therapy Approaches

• Gene replacement: Restore functional NONO expression
• CRISPR-based therapies: Correct disease-causing mutations
• Allele-specific silencing: Target toxic mutant alleles

Neuroprotective Strategies

• Stress granule modulators: Normalize stress response pathways
• DNA damage repair enhancers: Support genomic integrity
• Circadian rhythm stabilizers: Improve sleep and cellular homeostasis

Animal Models

Several models have been developed:

• NONO knockout mice: Viable with circadian rhythm defects
• Conditional knockout models: Motor neuron-specific deletion
• Transgenic models: Expressing human mutant NONO
• Knock-in models: Containing patient-specific mutations

Key Publications

Background

The identification of NONO mutations in ALS and FTD has expanded the spectrum of RNA-binding proteins implicated in neurodegenerative diseases. Together with TDP-43, FUS, and SFPQ, NONO represents a key member of the RNA metabolism pathway whose dysfunction leads to motor neuron degeneration. Research continues to elucidate the precise mechanisms and develop therapeutic interventions.

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=NONO+ALS+neurodegeneration) - Biomedical literature
• [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/4841) - Gene database entry
• [UniProt](https://www.uniprot.org/uniprot/Q13435) - Protein database entry
• [Allen Brain Atlas](https://human.brain-map.org/) - Brain gene expression data

See Also

• SFPQ Gene
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• RNA Splicing in Neurodegeneration
• Circadian Rhythm and Neurodegeneration

References

Pathway Diagram

The following diagram shows the key molecular relationships involving NONO Gene discovered through SciDEX knowledge graph analysis: