C9orf72 Dipeptide Repeat Proteins

C9orf72 Dipeptide Repeat Proteins

Overview

C9orf72 Dipeptide Repeat Proteins

Overview

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">C9orf72 Dipeptide Repeat Proteins</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>C9ORF72-DIPEPTIDE-REPEAT-PROTEINS</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>C9orf72 Dipeptide Repeats</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=C9ORF72-DIPEPTIDE-REPEAT-PROTEINS" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als/ftd" style="color:#ef9a9a">ALS/FTD</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">872 edges</a></td>
</tr>
</table>

[C9orf72](/entities/c9orf72) Dipeptide Repeat Proteins (DPRs) are toxic protein aggregates generated by the hexanucleotide repeat expansion (GGGGCC) in the C9orf72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)[@dejesushernandez2011]. The repeat expansion leads to the production of five different dipeptide repeat proteins through a non-ATG (RAN) translation mechanism: poly-GA, poly-GR, poly-PR, poly-PA, and poly-GP["@ash2013"]. These DPRs form insoluble inclusions in the brains and spinal cords of patients, contributing to neurodegeneration through multiple molecular mechanisms.

Molecular Biology

RAN Translation

The GGGGCC repeat expansion in the first intron of C9orf72 undergoes bidirectional transcription, producing both sense and antisense RNA transcripts that form nuclear RNA foci[@renton2011]. These expanded RNA repeats are translated in all three reading frames without a start codon, a process called Repeat-Associated Non-ATG (RAN) translation, generating the five DPR species[@zu2013]. RAN translation occurs in both the forward (sense) and reverse (antisense) directions, producing poly-GA (glycine-alanine), poly-GR (glycine-arginine), poly-PR (proline-arginine), poly-PA (proline-alanine), and poly-GP (glycine-proline) proteins.

Toxicity Mechanisms

The different DPR species exhibit distinct toxicities:

• Poly-GA: Forms the most abundant inclusions, disrupting proteostasis by sequestering ubiquitin and proteasomes[@zhang2014]
• Poly-GR/PR: Interfere with nucleocytoplasmic transport, bind to RNA-processing proteins, and cause nucleolar stress[@kwon2014]
• Poly-PA: Contributes to stress granule formation and liquid-liquid phase separation[@lee2016]

Role in Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

C9orf72-associated ALS accounts for approximately 40% of familial ALS cases and 5-10% of sporadic ALS[@majounie2012]. The DPRs contribute to motor neuron death through:

• RNA toxicity: RNA foci sequester RNA-binding proteins, disrupting normal RNA processing
• Protein toxicity: DPR inclusions impair cellular proteostasis and organelle function
• Loss of C9orf72 function: The repeat expansion reduces normal C9orf72 protein expression, affecting lysosomal and autophagic function[@frick2018]

Frontotemporal Dementia (FTD)

C9orf72 expansions are the most common cause of familial FTD, particularly the behavioral variant (bvFTD)[@rohrer2015]. DPR pathology is widespread in the frontal and temporal cortices, correlating with clinical symptoms.

C9orf72-ALS/FTD Spectrum

Many patients present with overlapping ALS-FTD syndromes, reflecting the shared pathophysiology of both diseases[@benussi2020]. The clinical phenotype depends on the distribution of pathology—motor [cortex](/brain-regions/cortex) involvement leads to ALS, while frontal/temporal involvement produces FTD.

Therapeutic Strategies

Antisense Oligonucleotides (ASOs)

Multiple ASO therapies are in development to suppress C9orf72 repeat RNA expression[@liu2019]. These ASOs target either the repeat RNA itself or the sense/antisense transcripts to reduce DPR production.

Small Molecule Inhibitors

Research efforts focus on developing RAN translation inhibitors and compounds that prevent DPR aggregation[@cheng2018].

Gene Therapy

CRISPR-based approaches to specifically edit or silence the expanded allele are under investigation[@pranav2022].

See Also

• [C9orf72 Gene](/genes/c9orf72)
• [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
• [RNA Toxicity in Neurodegeneration](/diseases/neurodegeneration)
• [Proteostasis in Neurodegeneration](/diseases/neurodegeneration)
• [ALS Genetics](/diseases/amyotrophic-lateral-sclerosis)

External Links

• [ALS Association - C9orf72 Research](https://www.als.org/)
• [Target ALS Foundation](https://www.targetals.org/)

References