C9orf72 DPR Protein

C9orf72 DPR Protein

Path: /proteins/c9orf72-dpr-protein Title: C9orf72 DPR Protein Tags: section:proteins, kind:protein

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8;">C9orf72 DPR Protein</th></tr>
<tr><td><b>Gene</b></td><td>[C9orf72](/entities/c9orf72)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q9NS67](https://www.uniprot.org/uniprot/Q9NS67)</td></tr>
<tr><td><b>PDB Structures</b></td><td>None available</td></tr>
<tr><td><b>Molecular Weight</b></td><td>Dipeptide repeats: 5-20 kDa</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cytoplasm, Nucleus</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>
</div>

Overview

The C9orf72 dipeptide repeat (DPR) proteins are toxic polyl glycine-proline (poly-GP) and poly-proline-alanine (poly-PA) species generated by unconventional translation of the hexanucleotide repeat expansion in the C9orf72 gene. This repeat expansion is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). [@corf]

C9orf72 DPR Protein

Path: /proteins/c9orf72-dpr-protein Title: C9orf72 DPR Protein Tags: section:proteins, kind:protein

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8;">C9orf72 DPR Protein</th></tr>
<tr><td><b>Gene</b></td><td>[C9orf72](/entities/c9orf72)</td></tr>
<tr><td><b>UniProt ID</b></td><td>[Q9NS67](https://www.uniprot.org/uniprot/Q9NS67)</td></tr>
<tr><td><b>PDB Structures</b></td><td>None available</td></tr>
<tr><td><b>Molecular Weight</b></td><td>Dipeptide repeats: 5-20 kDa</td></tr>
<tr><td><b>Subcellular Localization</b></td><td>Cytoplasm, Nucleus</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>
</div>

Overview

The C9orf72 dipeptide repeat (DPR) proteins are toxic polyl glycine-proline (poly-GP) and poly-proline-alanine (poly-PA) species generated by unconventional translation of the hexanucleotide repeat expansion in the C9orf72 gene. This repeat expansion is the most common genetic cause of both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). [@corf]

Pathogenic Mechanism

Repeat Expansion

• The GGGGCC hexanucleotide repeat expansion in the first intron of C9orf72
• Normal: < 30 repeats
• Pathogenic: hundreds to thousands of repeats
• Leads to three pathogenic mechanisms: [@hexanucleotide]

Dipeptide Repeat (DPR) Synthesis

DPR Protein Types

Five different dipeptide repeats are produced: [@dipeptide]

| Dipeptide | Reading Frame | Toxicity |
|-----------|---------------|-----------|
| Poly-GA | +1 frame | High |
| Poly-GP | +2 frame | Moderate |
| Poly-GR | +1 frame (antisense) | High |
| Poly-PR | +2 frame (antisense) | High |
| Poly-PA | +3 frame | Low |

Neurotoxicity Mechanisms

RNA Toxicity

• RNA foci sequester essential RNA-binding proteins
• Disrupts RNA splicing and trafficking
• Affects nucleocytoplasmic transport

DPR Toxicity [@mechanisms]

• Poly-GA: Forms inclusions, disrupts proteostasis
• Poly-GR/PR: Interferes with nucleocytoplasmic transport
• Nucleolar stress: DPRs accumulate in nucleolus
• Stress granule formation: Alters stress response

Loss of C9orf72 Function

• [Autophagy](/entities/autophagy)-lysosome pathway dysfunction
• Impaired trafficking of cellular proteins
• Altered immune response

Role in Neurodegeneration

Amyotrophic Lateral Sclerosis

• C9orf72 is the most common genetic cause of ALS
• Motor neuron degeneration through toxic DPRs
• RNA foci found in motor [neurons](/entities/neurons) of patients [@rna]

Frontotemporal Dementia

• [TDP-43](/mechanisms/tdp-43-proteinopathy) pathology co-occurs with DPR inclusions
• Frontotemporal lobar degeneration with motor neuron disease
• Behavioral variant FTD is common presentation

Co-pathology

• Both ALS and FTD can occur in the same patient
• Mixed pathology common in C9orf72 carriers
• DPRs found alongside TDP-43 and [tau](/proteins/tau) pathology

Therapeutic Strategies

Targeting RNA

• Antisense oligonucleotides (ASOs) to reduce repeat-containing RNA
• Small molecules to bind repeat RNA
• RNA foci dispersants

DPR-targeted Approaches [@therapeutic]

• Autophagy enhancers to clear DPR inclusions
• Small molecules to inhibit RAN translation
• Antibodies against specific DPR species

Gene Therapy

• CRISPR-based approaches to reduce repeat expansion
• Allele-specific silencing
• Increasing endogenous C9orf72 expression

Biomarkers

Fluid Biomarkers

• Poly-GP in cerebrospinal fluid (CSF)
• [Neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain (NfL) in blood
• Tau and amyloid markers

Imaging

• Frontal and temporal lobe atrophy on MRI
• Hypometabolism on FDG-PET
• White matter abnormalities on DTI

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References