| FUS Protein | |
|---|---|
| Gene | [FUS](/genes/fus) |
| UniProt | P35637 |
| PDB | 2LCW, 2YIO |
| Mol. Weight | 53 kDa |
| Localization | Nucleus, Cytoplasm |
| Family | FUS/TLS family (FET family) |
| Diseases | [Amyotrophic Lateral Sclerosis](/diseases/als), [Frontotemporal Dementia](/diseases/frontotemporal-dementia) |
FUS (Fused in Sarcoma/Translocated in Liposarcoma) is an RNA-binding protein encoded by the FUS gene that plays critical roles in RNA processing, transcription regulation, and DNA repair[1]. This protein belongs to the FET (FUS, EWS, TAF15) family of RNA-binding proteins and has a molecular weight of approximately 53 kDa[2]. FUS localizes to both the nucleus and cytoplasm, where it participates in various aspects of RNA metabolism including splicing, transport, and translation[3].
Mutations in FUS are a major cause of familial amyotrophic lateral sclerosis (ALS), accounting for approximately 4-5% of all ALS cases and up to 10% of cases with early onset[4]. FUS mutations also cause approximately 5-10% of familial frontotemporal dementia (FTD) cases, and there is substantial clinical and pathological overlap between ALS and FTD[5].
FUS participates in multiple aspects of RNA metabolism:
FUS functions as a transcriptional regulator:
In neurons, FUS is particularly important for:
Most pathogenic FUS mutations lead to toxic gain-of-function:
FUS forms cytoplasmic inclusions in affected neurons:
Motor neurons and cortical neurons show particular susceptibility:
Over 50 pathogenic mutations in FUS have been identified:
| Mutation Type | Common Mutations | Effect |
|---|---|---|
| Missense | R521C, R521H, R522G | Most common |
| Frameshift | Various | Often severe |
| Nonsense | Premature stop | Truncated protein |
FUS contains multiple functional domains:
| Domain | Amino Acids | Function |
|---|---|---|
| QGSY-rich | 1-214 | Low complexity, aggregation-prone |
| RRM | 285-371 | RNA recognition |
| RGG repeats | 385-526 | Arginine-glycine-glycine repeats |
| Zinc finger | 422-461 | RNA binding |
| NLS | 526-526 | Nuclear localization |
The low-complexity QGSY-rich domain drives liquid-liquid phase separation and stress granule formation[2:1].
FUS interacts with several other disease-related proteins:
| Protein | Interaction | Disease Relevance |
|---|---|---|
| TDP-43 | Co-aggregation | Shared pathology |
| C9orf72 | Genetic interaction | Common genetic causes |
| SOD1 | Common pathways | Parallel degeneration |
| OPTN | Autophagy regulation | Shared mechanisms |
| TBK1 | Kinase substrate | Shared signaling[16] |
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009. ↩︎ ↩︎
Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE. Mutations in FUS cause ALS. Science. 2009. ↩︎ ↩︎ ↩︎
Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain. 2009. ↩︎ ↩︎
Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016. ↩︎ ↩︎
Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013. ↩︎ ↩︎
Kapeli K, Martinez FJ, Yeo GW. Genetic mutations in RNA-binding proteins and their roles in disease. Wiley Interdisciplinary Reviews: RNA. 2017. ↩︎
Dormann D, Haass C. TDP-43 and FUS: a nuclear affair. Trends in Neurosciences. 2011. ↩︎
Monahan Z, Shewmaker F, Pandey UB. Stress granules in disease pathogenesis. Future Medicinal Chemistry. 2016. ↩︎
Barmada SJ, Skibinski G, Korb E, Rao EJ, Wu JY, Finkbeiner S. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and requires zinc finger domain. Journal of Neuroscience. 2012. ↩︎
Suzuki H, Matsuoka M. FUS toxicity is rescued by nuclear importin α2. Neurobiology of Aging. 2013. ↩︎
Lattante S, Rouleau GA, Kabashi E. TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary of current animal models and perspectives. ALS. 2013. ↩︎
Conte A, Lattante S, Zollino M, Marangi G, Luigetti M, Del Grande A, Servidei S, Tonali PA, Sabatelli M. P525L FUS mutation is consistently associated with a severe form of juvenile ALS. Neurobiology of Aging. 2012. ↩︎
Korobeynikov VA, Borodinov A, Burley J, Lyashkov A, Shuvalova L, Kaehler M, Isacson O. Gene therapy approaches for FUS-ALS. Cell Stem Cell. 2022. ↩︎
Chen Y, Cohen TJ. Aggregation of RNA-binding proteins in ALS/FTD. Trends in Cell Biology. 2021. ↩︎
Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC. [Amyotrophic lateral sclerosis](https://doi.org/10.1016/S0140-6736(11). Lancet. 2011. ↩︎
Liu Y, Zhou Q, Wang Y. C9orf72 and FUS: shared genetic mechanisms in ALS/FTD. Nature Reviews Neurology. 2016. ↩︎
Mitchell JC, McGough A, Wei J, Coleman VA, Farmer R, Woodman P, Gillingwater TH. Drosophila models of FUSopathies. Neurobiology of Disease. 2013. ↩︎