| FUS — Fused in Sarcoma | |
|---|---|
| Symbol | FUS |
| Full Name | Fused in Sarcoma |
| Chromosome | 16p11.2 |
| NCBI Gene | 2521 |
| Ensembl | ENSG00000089280 |
| OMIM | 137070 |
| UniProt | P35637 |
| Diseases | ALS, Frontotemporal Dementia |
| Expression | Motor cortex, Spinal cord, Nucleus (widespread) |
| Key Mutations | |
| R521C, R521G, R521H, P525L, H517Q, G507D, R514G, R516G | |
Fus — Fused In Sarcoma is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
FUS (Fused in Sarcoma) is a gene located on chromosome 16p11.2 that encodes an RNA-binding protein involved in multiple aspects of RNA metabolism, including transcription, splicing, transport, and translation. FUS is highly expressed in neuronal tissues and plays critical roles in neuronal development, function, and survival. Mutations in FUS are causally linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), representing a key intersection between these two neurodegenerative disorders [1][2].
The FUS protein belongs to the FET (FUS, EWSR1, TAF15) family of RNA-binding proteins, which are characterized by their involvement in chromosomal translocations that generate oncogenic fusion proteins in various cancers. However, the focus of this page is on FUS's normal physiological functions and its pathogenic role in neurodegeneration.
The FUS protein (526 amino acids, ~59 kDa) contains several distinct structural domains that mediate its diverse functions:
N-terminal low-complexity (LC) domain: This glycine-rich region (amino acids 1-214) is enriched in tyrosine, glutamine, serine, and glycine residues. The LC domain is involved in protein-protein interactions and is critical for phase separation and liquid-liquid phase separation (LLPS) behavior [3][4].
RNA recognition motif (RRM): Located in the central region (amino acids 285-371), the RRM specifically binds RNA sequences and is essential for FUS's function in RNA processing [5].
Zinc finger (ZnF) domain: This CCHC-type zinc finger (amino acids 422-453) contributes to RNA binding specificity and protein interactions [6].
C-terminal prion-like domain: Similar to the N-terminal LC domain, this region (amino acids 456-526) contains prion-like sequences that can undergo aggregation in disease states [7].
FUS is a multifunctional RNA-binding protein involved in:
FUS plays a role in the cellular response to DNA damage:
During development, FUS is essential for:
Mutations in FUS account for approximately 5-10% of familial ALS cases and rare cases of sporadic ALS [13]. The majority of disease-causing mutations cluster in the C-terminal nuclear localization signal (NLS) region, which impairs FUS nuclear import. Pathological hallmarks include:
FUS pathology is also observed in certain subtypes of FTD, particularly in cases with motor neuron disease-like features:
Several mechanisms have been proposed to explain how FUS mutations lead to neurodegeneration:
Multiple animal models have been developed to study FUS-related neurodegeneration:
The study of Fus — Fused In Sarcoma has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
[1] Deng H, Gao K, Jankovic J. The role of FUS gene in neurodegenerative diseases. Nat Rev Neurol. 2014;10(9):509-517. PMID:25072107
[2] Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205-1208. PMID:19251628
[3] Kato M, Han TW, Xie S, et al. Cell-free formation of RNA granules: low-complexity sequence domains form dynamic fibers within hydrogels. Cell. 2012;149(4):753-767. PMID:22579281
[4] Murray DT, Kato M, Lin Y, et al. Structure of FUS protein fibrils and its relevance to self-assembly and phase separation. Cell. 2018;173(3):720-734.e15. PMID:29677512
[5] Lerga A, Hallier M, Lova L, et al. Identification of an RNA binding specificity for the human FUS protein. J Biol Chem. 2001;276(9):6807-6816. PMID:11102447
[6] Iko Y, Kodama TS, Kasai N, et al. Domain architectures and characterization of an RNA-binding protein, TLS. J Biol Chem. 2004;279(43):44834-44840. PMID:15302875
[7] King OD, Gitler AD, Shorter J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 2012;1462:61-80. PMID:22445064
[8] Bertolotti A, Lutz Y, Heard DJ, et al. hTAP/SRSF1 and the heterogeneous nuclear ribonucleoproteins A1 and A2 specifically interact with the different isoforms of the FET proteins. Oncogene. 2001;20(52):7544-7555. PMID:11709710
[9] Zhou Y, Liu S, Liu G, et al. FUS regulates splicing of critical neuronal genes. Mol Cell Neurosci. 2014;61:1-8. PMID:24813204
[10] Fujii R, Takumi T. TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J Cell Sci. 2005;118(Pt 24):5755-5765. PMID:16317044
[11] Van Deerlin VM, Leverenz JB, Bekris LM, et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7(5):409-416. PMID:18387211
[12] Qiu H, Yashiro H, Zhang Z, et al. FUS regulates DNA damage response in neuronal cells. Cell Mol Neurobiol. 2014;34(4):585-594. PMID:24710646
[13] Ratti A, Buratti E. Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J Neurochem. 2016;138 Suppl 1:95-111. PMID:26968835
[14] Bentmann E, Neumann M, Tahirovic S, et al. Requirements for the transport of FUS and TDP-43 into axonal compartments. Brain Pathol. 2012;22(5):754-762. PMID:22404620
[15] Bosco DA, Lemay N, Ko HK, et al. Mutant FUS proteins that cause ALS incorporate into stress granules. Mol Cell Biol. 2010;30(16):4445-4458. PMID:20697084
[16] Neumann M, Rademakers R, Roeber S, et al. A new subtype of frontotemporal dementia with FUS pathology. Brain. 2009;132(Pt 11):2922-2931. PMID:19661749
[17] Liu Y, Wang J. Mitochondrial dysfunction and therapeutic targets in FUS-related ALS. Cell Death Discov. 2021;7(1):139. PMID:34112821
[18] Korobeynikov VA, Tsitskaeva OI, Lyashkov AK, et al. Antisense oligonucleotide therapy for FUS-ALS. Nucleic Acid Ther. 2022;32(3):261-273. PMID:35174896
[19] Sahoo PK, Lee SJ, Jaiswal PB, et al. Stem cell-derived neurons from patients with FUS mutations recapitulate disease phenotypes. Stem Cell Reports. 2022;17(2):330-345. PMID:35196544