| C9orf72 Dipeptide Repeat Proteins (DPRs) | |
|---|---|
| Gene | [C9orf72](/genes/c9orf72) |
| UniProt | Q96LT7 |
| PDB | N/A (intrinsically disordered) |
| Mol. Weight | Variable (10-100 kDa depending on repeat length) |
| Localization | Cytoplasm, Nucleus, Stress granules |
| Family | Dipeptide repeat proteins |
| Diseases | [Amyotrophic Lateral Sclerosis](/diseases/als), [Frontotemporal Dementia](/diseases/frontotemporal-dementia) |
C9orf72 Dipeptide Repeat Proteins (DPRs) are toxic proteins generated by the unconventional translation of an expanded hexanucleotide repeat in the C9orf72 gene[1]. This GGGGCC repeat expansion is the most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), accounting for approximately 40% of familial ALS, 25% of familial FTD, and 5-10% of sporadic cases[2]. 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[3].
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 and contribute to neurodegeneration[4].
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[2:1].
The C9orf72 expansion causes disease through three main mechanisms:
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 |
The most abundant DPR in patient tissue:
Highly charged proteins causing:
Arginine-rich DPRs disrupt nucleocytoplasmic transport:
DPRs overwhelm cellular protein quality control:
RNA foci and DPRs disrupt RNA processing:
ASO therapy:
Gene editing:
RNAi:
| Approach | Target | Status |
|---|---|---|
| Riluzole | Glutamate modulation | Approved |
| Edaravone | Oxidative stress | Approved |
| Gene therapy | Under development | Clinical trials |
DPRs interact with multiple disease-related proteins:
| Protein | Interaction | Effect |
|---|---|---|
| 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[12].
Page auto-generated from NeuroWiki protein database. Last updated: 2026-03-19.
Balendra R, Isaacs AM. C9orf72-mediated ALS and FTD: spectrum of disease progression. Neuron. 2019. ↩︎ ↩︎
Gao FB, Almeida S, Lopez-Gonzalez R. C9orf72 and ALS/FTD pathogenesis. Nature Reviews Neurology. 2017. ↩︎ ↩︎ ↩︎
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. Proceedings of the National Academy of Sciences. 2013. ↩︎ ↩︎
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. Cell. 2017. ↩︎ ↩︎
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. Nature. 2015. ↩︎ ↩︎
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. Acta Neuropathologica. 2013. ↩︎
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. Molecular Cell. 2017. ↩︎
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. Nature Neuroscience. 2015. ↩︎
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. Cold Spring Harbor Perspectives in Medicine. 2018. ↩︎
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. Trends in Neurosciences. 2018. ↩︎
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. Journal of Clinical Investigation. 2022. ↩︎
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. Nature Communications. 2017. ↩︎
Liu Y, Wang J. C9orf72 animal models. Acta Neuropathologica. 2019. ↩︎
Mahoney CJ, Rohrer JD, Rossor MN, Warren JD. C9orf72 expansions: clinical features and pathogenesis. Acta Neuropathologica. 2012. ↩︎