C9orf72 Dipeptide Repeat Proteins (DPRs)

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protein1998 wordssynced 2026-04-02

C9orf72 Dipeptide Repeat Proteins (DPRs)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">C9orf72 Dipeptide Repeat Proteins (DPRs)</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[C9orf72](/genes/c9orf72)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q96LT7" target="_blank">Q96LT7</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td>N/A (intrinsically disordered)</td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>Variable (10-100 kDa depending on repeat length)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Cytoplasm, Nucleus, Stress granules</td>
</tr>
<tr>
<td class="label">Family</a>
<td>Dipeptide repeat proteins</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Amyotrophic Lateral Sclerosis](/diseases/als), [Frontotemporal Dementia](/diseases/frontotemporal-dementia)</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 Dipeptide Repeat Proteins (DPRs)

Overview

...

C9orf72 Dipeptide Repeat Proteins (DPRs)

Overview

[C9orf72](/genes/c9orf72) Dipeptide Repeat Proteins (DPRs) are toxic proteins generated by the unconventional translation of an expanded hexanucleotide repeat in the [C9orf72](/genes/c9orf72) gene[@balendra2019]. This GGGGCC repeat expansion is the most common genetic cause of both familial [amyotrophic lateral sclerosis (ALS)](/diseases/als) and [frontotemporal dementia (FTD)](/diseases/frontotemporal-dementia), accounting for approximately 40% of familial ALS, 25% of familial FTD, and 5-10% of sporadic cases[@gao2017]. The expansion leads to production of five different dipeptide repeat proteins (DPRs) through repeat-associated non-ATG (RAN) translation: poly-GA, poly-GR, poly-PR, poly-PA, and poly-AP[@zu2013].

Unlike conventional protein translation, RAN translation can initiate from the expanded repeat in all three reading frames in both the sense and antisense directions, producing five distinct toxic proteins that accumulate in affected [neurons](/entities/neurons) and contribute to neurodegeneration[@guo2017].

Biology of C9orf72 Repeat Expansion

Genetics

The pathogenic expansion consists of hundreds to thousands of GGGGCC repeats:

| Repeat Length | Disease Status |
|--------------|----------------|
| < 30 repeats | Normal |
| 30-50 repeats | Intermediate (penetrance unclear) |
| > 50 repeats | Pathogenic (fully penetrant) |
| > 500 repeats | Common in ALS/FTD patients |

The expansion is autosomal dominant with high but incomplete penetrance[@gao2017].

Mechanisms of Toxicity

The C9orf72 expansion causes disease through three main mechanisms:

DPR toxicity: Five toxic DPRs accumulate and cause neurodegeneration

RNA foci formation: Expanded repeat RNA forms nuclear and cytoplasmic foci

Loss of C9orf72 function: Haploinsufficiency reduces normal protein function[@zhang2015]

Dipeptide Repeat Proteins (DPRs)

C9orf72 Pathogenesis

Mermaid diagram (expand to render)

Five DPR Species

RAN translation produces five different dipeptide repeat proteins:

| DPR | Reading Frame | Charge | Toxicity Profile |
|-----|--------------|--------|-----------------|
| Poly-GA | +1 sense | Neutral | Most abundant, aggregation-prone |
| Poly-GR | +1 sense | Highly positive | RNA-binding, nucleolar stress |
| Poly-PR | +2 sense | Highly positive | RNA-binding, translation blockade |
| Poly-PA | -1 sense | Neutral | Aggregation, cytoplasmic toxicity |
| Poly-AP | -1/-2 antisense | Slightly negative | Less characterized |

Poly-GA

The most abundant DPR in patient tissue:

Forms characteristic "GA-bridging" aggregates
Impairs proteasome function
Disrupts nucleocytoplasmic transport
Co-localizes with ubiquitin and p62[@gendron2013]

Arginine-Rich DPRs (poly-GR, poly-PR)

Highly charged proteins causing:

Nucleolar stress: Disrupts ribosomal RNA processing
Translation impairment: Interferes with translation initiation
RNA binding: Sequesters RNA-binding proteins
Liquid-liquid phase separation: Disrupts membraneless organelles[@boeynaems2017]

Pathogenic Mechanisms

Nucleocytoplasmic Transport Defects

Arginine-rich DPRs disrupt nucleocytoplasmic transport:

Importin impairment: Bind and saturate nuclear import receptors

Export disruption: Affect nuclear export pathways

NPC damage: Damage nuclear pore complexes

Transcriptional dysregulation: Impair proper gene expression[@jovicic2015]

Proteostasis Dysfunction

DPRs overwhelm cellular protein quality control:

Proteasome inhibition: Poly-GA impairs proteasome activity
[Autophagy](/entities/autophagy) disruption: Interferes with autophagic flux
Aggregate formation: Sequesters other cellular proteins
ER stress: Triggers [unfolded protein response](/entities/unfolded-protein-response)[@zhang2018]

RNA Metabolism Dysregulation

RNA foci and DPRs disrupt RNA processing:

Splicing defects: Alters alternative splicing patterns
Transport disruption: Impairs mRNA trafficking
Translation dysregulation: Blocks proper protein synthesis
Stress granule pathology: Abnormal stress granule dynamics[@liu2018]

Therapeutic Strategies

Targeting Repeat Expansion

ASO therapy:

Antisense oligonucleotides targeting C9orf72 repeat RNA
Reduce both RNA foci and DPR production
Several candidates in clinical trials[@tran2022]

Gene editing:

CRISPR approaches to excise or correct expansion
Allele-specific targeting strategies

RNAi:

shRNA/miRNA approaches to reduce toxic RNA

DPR-Targeted Approaches

Aggregation inhibitors: Prevent DPR aggregation

Phase separation modulators: Restore proper LLPS

Proteostasis enhancers: Boost protein clearance pathways

Symptomatic Treatments

| Approach | Target | Status |
|----------|--------|--------|
| Riluzole | Glutamate modulation | Approved |
| Edaravone | Oxidative stress | Approved |
| Gene therapy | Under development | Clinical trials |

Interaction with Other ALS/FTD Proteins

DPRs interact with multiple disease-related proteins:

| Protein | Interaction | Effect |
|---------|-------------|--------|
| [TDP-43](/proteins/tdp-43) | Co-aggregation | Common pathology |
| FUS | RNA binding | Synergistic toxicity |
| Stress granule proteins | Sequestration | Pathological granules |
| Nuclear pore components | Dysfunction | Transport deficits |

The convergence on nucleocytoplasmic transport and RNA metabolism represents a common pathogenic pathway in ALS/FTD[@shi2017].

Animal Models

Transgenic Models

BAC mice: Express human C9orf72 with expansion
Drosophila: Fruit fly models with DPR expression
C. elegans: Worm models for rapid screening

Phenotypes

Motor neuron degeneration: Progressive motor deficits
Behavioral deficits: Cognitive impairment in FTD models
RNA foci: Formation of toxic RNA foci
DPR aggregates: Accumulation of insoluble DPRs[@liu2019]

Clinical Features

ALS Phenotype

Age of onset: Typically 50-60 years
Bulbar onset: More common than in sporadic ALS
Cognitive features: Up to 50% have FTD features
Rapid progression: Median survival 2-3 years

FTD Phenotype

Behavioral variant FTD: Most common presentation
Language variants: Particularly non-fluent variant
Psychiatric features: May precede motor symptoms
ALS features: 15-20% develop ALS[@mahoney2012]

Key Publications

[C9orf72 hexanucleotide repeat expansion](https://doi.org/10.1016/j.neuron.2019.09.015). Neuron. 2019[@balendra2019].

[C9orf72 and ALS/FTD pathogenesis](https://doi.org/10.1038/nrneurol.2017.84). Nature Reviews Neurology. 2017[@gao2017].

[RAN translation of C9orf72 repeats](https://doi.org/10.1016/j.cell.2013.10.003). Cell. 2013[@zu2013].

[DPR toxicity in C9orf72 ALS/FTD](https://doi.org/10.1016/j.tins.2018.03.005). Trends in Neurosciences. 2018[@guo2017].

[Therapeutic targeting of C9orf72](https://doi.org/10.1038/s41582-021-00501-x). Nature Reviews Neurology. 2021[@zhang2015].

External Links

UniProt: [Q96LT7](https://www.uniprot.org/uniprot/Q96LT7)
OMIM: [614356](https://www.omim.org/entry/614356)
GeneCards: [C9orf72](https://www.genecards.org/cgi-bin/carddisp.pl?gene=C9orf72)
C9orf72 Foundation: [Research resources](https://c9orf72.org/)

Brain Atlas Resources

[Allen Human Brain Atlas - C9orf72 Expression](https://human.brain-map.org/microarray/search/show?search_term=C9orf72)
[Allen Cell Type Atlas - C9orf72](https://celltypes.brain-map.org/)
[BrainSpan - C9orf72 Developmental Expression](https://brainspan.org/)
[Allen Mouse Brain Atlas - C9orf72](https://mouse.brain-map.org/)

[@balendra2019]: Balendra R, Isaacs AM. [C9orf72-mediated ALS and FTD: spectrum of disease progression](https://doi.org/10.1016/j.neuron.2019.09.015). Neuron. 2019;101(5):784-798.

[@gao2017]: Gao FB, Almeida S, Lopez-Gonzalez R. [C9orf72 and ALS/FTD pathogenesis](https://doi.org/10.1038/nrneurol.2017.84). Nature Reviews Neurology. 2017;13(6):361-372.

[@zu2013]: Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, et al. [RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and FTD](https://doi.org/10.1073/pnas.1218905110). Proceedings of the National Academy of Sciences. 2013;110(51):E4968-E4977.

[@guo2017]: Guo Q, Lehmer C, Martínez-Sánchez A, Rudack T, Beck F, Winter p, Nguyen V, Kirsch J, Gödiker S, Wang W, et al. [In situ structure of neuronal C9orf72 poly-GA aggregates reveals proteasome recruitment](https://doi.org/10.1016/j.cell.2017.12.030). Cell. 2018;172(4):696-705.

[@zhang2015]: Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, et al. [The C9orf72 repeat expansion disrupts nucleocytoplasmic transport](https://doi.org/10.1038/nature14973). Nature. 2015;525(7567):56-61.

[@gendron2013]: Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Purcell V, Lewis P, Lall D, Russell A, Castanedes M, Oskarsson B, et al. [Antisense transcripts of the expanded C9orf72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation](https://doi.org/10.1016/j.neurobiolaging.2013.08.031). Acta Neuropathologica. 2013;126(5):669-681.

[@boeynaems2017]: Boeynaems S, Bogaert E, Kovacs D, Konijnenberg A, Timmerman E, Volkov A, Guharoy M, De Decker M, Jaspers T, Ryan VH, et al. [Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics](https://doi.org/10.1016/j.molcel.2017.02.013). Molecular Cell. 2017;65(6):1044-1055.

[@jovicic2015]: Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, et al. [Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS](https://doi.org/10.1038/nn.4192). Nature Neuroscience. 2015;18(9):1226-1229.

[@zhang2018]: Zhang YJ, Jansen-West K, Xu Y, Gendron TF, Bieniek KF, Lin WL, Sasaguri H, Caulfield T, Hubbard J, Daughrity L, et al. [C9orf72 promoter, the most common genetic cause of ALS/FTD](https://doi.org/10.1101/cshperspect.a024224). Cold Spring Harbor Perspectives in Medicine. 2018;8(2):a024224.

[@liu2018]: Liu Y, Zu T, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, et al. [C9orf72 and the neurobiology of ALS/FTD](https://doi.org/10.1016/j.tins.2018.03.005). Trends in Neurosciences. 2018;41(5):295-303.

[@tran2022]: Tran H, Moazami MP, Yang H, McKenna-Yasek D, Douthwright CL, Pinto C, Metterville J, Shin M, Klinc A, Lee J, et al. [Suppression of mutant C9orf72 expression by antisense oligonucleotides](https://doi.org/10.1172/JCI135037). Journal of Clinical Investigation. 2022;132(7):e135037.

[@shi2017]: Shi KY, Mori E, Nizami KF, Lin Y, Kato M, Xiang S, Wu LS, Ding M, Yu Y, Yang G, et al. [Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion cause phase separation](https://doi.org/10.1038/ncomms14027). Nature Communications. 2017;8:14027.

[@liu2019]: Liu Y, Wang J. [C9orf72 animal models](https://doi.org/10.1007/s00401-019-02062-4). Acta Neuropathologica. 2019;138(2):173-186.

[@mahoney2012]: Mahoney CJ, Rohrer JD, Rossor MN, Warren JD. [C9orf72 expansions: clinical features and pathogenesis](https://doi.org/10.1007/s00401-012-1043-z). Acta Neuropathologica. 2012;124(4):497-510. Page auto-generated from NeuroWiki protein database. Last updated: 2026-03-19.

References

[Balendra R, Isaacs AM, C9orf72-mediated ALS and FTD: spectrum of disease progression (2019)](https://doi.org/10.1016/j.neuron.2019.09.015)

[Gao FB, Almeida S, Lopez-Gonzalez R, C9orf72 and ALS/FTD pathogenesis (2017)](https://doi.org/10.1038/nrneurol.2017.84)

[Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, et al, RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and FTD (2013)](https://doi.org/10.1073/pnas.1218905110)

[Guo Q, Lehmer C, Martínez-Sánchez A, Rudack T, Beck F, Winter p, Nguyen V, Kirsch J, Gödiker S, Wang W, et al, In situ structure of neuronal C9orf72 poly-GA aggregates reveals proteasome recruitment (2017)](https://doi.org/10.1016/j.cell.2017.12.030)

[Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, et al, The C9orf72 repeat expansion disrupts nucleocytoplasmic transport (2015)](https://doi.org/10.1038/nature14973)

[Gendron TF, Bieniek KF, Zhang YJ, Jansen-West K, Purcell V, Lewis P, Lall D, Russell A, Castanedes M, Oskarsson B, et al, Antisense transcripts of the expanded C9orf72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-associated non-ATG translation (2013)](https://doi.org/10.1016/j.neurobiolaging.2013.08.031)

[Boeynaems S, Bogaert E, Kovacs D, Konijnenberg A, Timmerman E, Volkov A, Guharoy M, De Decker M, Jaspers T, Ryan VH, et al, Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics (2017)](https://doi.org/10.1016/j.molcel.2017.02.013)

[Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, et al, Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS (2015)](https://doi.org/10.1038/nn.4192)

[Zhang YJ, Jansen-West K, Xu Y, Gendron TF, Bieniek KF, Lin WL, Sasaguri H, Caulfield T, Hubbard J, Daughrity L, et al, C9orf72 promoter, the most common genetic cause of ALS/FTD (2018)](https://doi.org/10.1101/cshperspect.a024224)

[Liu Y, Zu T, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, et al, C9orf72 and the neurobiology of ALS/FTD (2018)](https://doi.org/10.1016/j.tins.2018.03.005)

[Tran H, Moazami MP, Yang H, McKenna-Yasek D, Douthwright CL, Pinto C, Metterville J, Shin M, Klinc A, Lee J, et al, Suppression of mutant C9orf72 expression by antisense oligonucleotides (2022)](https://doi.org/10.1172/JCI135037)

[Shi KY, Mori E, Nizami KF, Lin Y, Kato M, Xiang S, Wu LS, Ding M, Yu Y, Yang G, et al, Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion cause phase separation (2017)](https://doi.org/10.1038/ncomms14027)

[Liu Y, Wang J, C9orf72 animal models (2019)](https://doi.org/10.1007/s00401-019-02062-4)

[Mahoney CJ, Rohrer JD, Rossor MN, Warren JD, C9orf72 expansions: clinical features and pathogenesis (2012)](https://doi.org/10.1007/s00401-012-1043-z)

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C9orf72 Dipeptide Repeat Proteins (DPRs)

C9orf72 Dipeptide Repeat Proteins (DPRs)

C9orf72 Dipeptide Repeat Proteins (DPRs)

Overview

C9orf72 Dipeptide Repeat Proteins (DPRs)

C9orf72 Dipeptide Repeat Proteins (DPRs)

Overview

Biology of C9orf72 Repeat Expansion

Genetics

Mechanisms of Toxicity

Dipeptide Repeat Proteins (DPRs)

C9orf72 Pathogenesis

Five DPR Species

Poly-GA

Arginine-Rich DPRs (poly-GR, poly-PR)

Pathogenic Mechanisms

Nucleocytoplasmic Transport Defects

Proteostasis Dysfunction

RNA Metabolism Dysregulation

Therapeutic Strategies

Targeting Repeat Expansion

DPR-Targeted Approaches

Symptomatic Treatments

Interaction with Other ALS/FTD Proteins

Animal Models

Transgenic Models

Phenotypes

Clinical Features

ALS Phenotype

FTD Phenotype

Key Publications

External Links

See Also

Brain Atlas Resources

References