FUS Protein

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FUS Protein

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FUS Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">FUS Protein</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[FUS](/genes/fus)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P35637" target="_blank">P35637</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/2LCW" target="_blank">2LCW</a>, <a href="https://www.rcsb.org/structure/2YIO" target="_blank">2YIO</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>53 kDa</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Nucleus, Cytoplasm</td>
</tr>
<tr>
<td class="label">Family</td>
<td>FUS/TLS family (FET family)</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/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">719 edges</a></td>
</tr>
</table>

FUS Protein

Overview

...

FUS Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">FUS Protein</th>
</tr>
<tr>
<td class="label">Gene</td>
<td>[FUS](/genes/fus)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P35637" target="_blank">P35637</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/2LCW" target="_blank">2LCW</a>, <a href="https://www.rcsb.org/structure/2YIO" target="_blank">2YIO</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>53 kDa</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Nucleus, Cytoplasm</td>
</tr>
<tr>
<td class="label">Family</td>
<td>FUS/TLS family (FET family)</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/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">719 edges</a></td>
</tr>
</table>

FUS Protein

Overview

FUS (Fused in Sarcoma/Translocated in Liposarcoma) is an RNA-binding protein encoded by the [FUS](/genes/fus) gene that plays critical roles in RNA processing, transcription regulation, and DNA repair[@kwiatkowski2009]. This protein belongs to the FET (FUS, EWS, TAF15) family of RNA-binding proteins and has a molecular weight of approximately 53 kDa[@vance2009]. FUS localizes to both the nucleus and cytoplasm, where it participates in various aspects of RNA metabolism including splicing, transport, and translation[@neumann2009].

Mutations in [FUS](/genes/fus) are a major cause of familial [amyotrophic lateral sclerosis (ALS)](/diseases/als), accounting for approximately 4-5% of all ALS cases and up to 10% of cases with early onset[@taylor2016]. FUS mutations also cause approximately 5-10% of familial [frontotemporal dementia (FTD)](/diseases/frontotemporal-dementia) cases, and there is substantial clinical and pathological overlap between ALS and FTD[@ling2013].

Normal Physiological Function

RNA Processing

FUS participates in multiple aspects of RNA metabolism:

Alternative splicing: Regulates splicing of numerous neuronal transcripts
RNA transport: Facilitates transport of mRNAs along axons
RNA stability: Modulates mRNA stability and decay
Translation regulation: Influences both translation initiation and elongation[@kapeli2017]

Transcriptional Regulation

FUS functions as a transcriptional regulator:

DNA damage response: Interacts with DNA repair complexes
Transcription factors: Interacts with various transcription factors including [NF-κB](/entities/nf-kb)
Chromatin remodeling: Associates with chromatin-modifying enzymes
RNA polymerase II: Modulates transcriptional elongation[@dormann2011]

Neuronal Functions

In [neurons](/entities/neurons), FUS is particularly important for:

Synaptic plasticity: Regulates local protein synthesis at synapses
Axon guidance: Involved in axonal outgrowth and pathfinding
Neuronal development: Critical for proper neuronal differentiation
Stress granules: Forms stress granules under cellular stress[@monahan2016]

Pathogenic Mechanisms in ALS/FTD

Gain-of-Function

Most pathogenic FUS mutations lead to toxic gain-of-function:

Cytoplasmic mislocalization: Mutations disrupt nuclear localization signals

Stress granule formation: Enhanced aggregation in stress granules

RNA processing defects: Altered splicing of critical neuronal transcripts

Axonal transport deficits: Impaired transport of RNA granules[@barmada2012]

Aggregation

FUS forms cytoplasmic inclusions in affected neurons:

ALS-FUS: Characteristic basophilic inclusions
FTD-FUS: FUS-positive inclusions in frontotemporal [cortex](/brain-regions/cortex)
Co-aggregation: May recruit other RNA-binding proteins
Sequestration: May sequester normal FUS and other proteins[@suzuki2013]

Selective Vulnerability

Motor neurons and cortical neurons show particular susceptibility:

Motor neurons: Both upper and lower motor neurons affected
Cortical layer 5 neurons: Degeneration in FTD
Pyramidal tract: Axonal degeneration in corticospinal tract
Neurophysiology: Evidence of combined upper/lower motor neuron signs[@lattante2013]

Mutations and Genotype-Phenotype Correlation

ALS-Causing Mutations

Over 50 pathogenic mutations in [FUS](/genes/fus) have been identified:

| Mutation Type | Common Mutations | Effect |
|--------------|------------------|--------|
| Missense | R521C, R521H, R522G | Most common |
| Frameshift | Various | Often severe |
| Nonsense | Premature stop | Truncated protein |

Genotype-Phenotype Relationships

R521C: Classic ALS, typical age of onset 40-60 years
P525L: Early onset, rapid progression
R521G: Often associated with FTD features[@conte2012]

Therapeutic Strategies

Gene Therapy Approaches

ASO therapy: Antisense oligonucleotides targeting FUS mRNA

Gene editing: CRISPR approaches to correct mutations

Allele-specific silencing: Targeting mutant allele specifically[@korobeynikov2022]

Small Molecule Approaches

Aggregation inhibitors: Compounds preventing FUS aggregation

Stress granule modulators: Agents modulating stress granule dynamics

RNA processing modifiers: Compounds improving splicing defects[@chen2021]

Neuroprotective Strategies

Riluzole: May provide modest benefit

Edaravone: Antioxidant, approved for ALS

Supportive care: Respiratory support, nutritional management[@kiernan2011]

Structure and Biochemistry

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[@vance2009].

Interaction with Other ALS/FTD Proteins

FUS interacts with several other disease-related proteins:

| Protein | Interaction | Disease Relevance |
|---------|-------------|-------------------|
| [TDP-43](/proteins/tdp-43) | Co-aggregation | Shared pathology |
| [C9orf72](/genes/c9orf72) | Genetic interaction | Common genetic causes |
| SOD1 | Common pathways | Parallel degeneration |
| OPTN | [Autophagy](/entities/autophagy) regulation | Shared mechanisms |
| TBK1 | Kinase substrate | Shared signaling[@liu2016] |

Animal Models

Mouse Models

FUS transgenic mice: Express mutant human FUS
Knock-in models:引入 disease-causing mutations
Conditional models: Spatiotemporal control of expression

Cellular Models

iPSC-derived neurons: Motor neurons from patient iPSCs
Organoids: Brain organoids showing FUS pathology
Fly models: Drosophila FUS models[@mitchell2013]

Key Publications

[FUS is mutated in familial amyotrophic lateral sclerosis](https://doi.org/10.1126/science.1166066). Science. 2009[@kwiatkowski2009].

[Structure and function of the FUS protein](https://doi.org/10.1016/j.tibs.2010.08.004). Trends in Biochemical Sciences. 2010[@vance2009].

[FUS pathology in ALS and FTD](https://doi.org/10.1007/s00401-011-0838-7). Acta Neuropathologica. 2011[@neumann2009].

[ALS genetics and mechanisms: FUS/TLS](https://doi.org/10.1016/j.neuron.2013.08.027). Neuron. 2013[@taylor2016].

[FUS-linked ALS and FTD: new insights into disease mechanisms](https://doi.org/10.1038/nrneurol.2017.35). Nature Reviews Neurology. 2017[@ling2013].

Pathway & Interaction Diagram

Interactive diagram showing FUS key relationships in the SciDEX knowledge graph (15 connections shown).

Mermaid diagram (expand to render)

External Links

UniProt: [P35637](https://www.uniprot.org/uniprot/P35637)
AlphaFold: [FUS](https://alphafold.ebi.ac.uk/entry/P35637)
PDB: [2LCW](https://www.rcsb.org/structure/2LCW)
OMIM: [137070](https://www.omim.org/entry/137070)
GeneCards: [FUS](https://www.genecards.org/cgi-bin/carddisp.pl?gene=FUS)

Brain Atlas Resources

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

References

[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 (2009)](https://doi.org/10.1126/science.1166066)

[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 (2009)](https://doi.org/10.1126/science.1165942)

[Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR, A new subtype of frontotemporal lobar degeneration with FUS pathology (2009)](https://doi.org/10.1007/s00401-009-0581-5)

[Taylor JP, Brown RH Jr, Cleveland DW, Decoding ALS: from genes to mechanism (2016)](https://doi.org/10.1038/nature20413)

[Ling SC, Polymenidou M, Cleveland DW, Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis (2013)](https://doi.org/10.1016/j.neuron.2013.10.047)

[Kapeli K, Martinez FJ, Yeo GW, Genetic mutations in RNA-binding proteins and their roles in disease (2017)](https://doi.org/10.1002/wmg3.333)

[Dormann D, Haass C, TDP-43 and FUS: a nuclear affair (2011)](https://doi.org/10.1016/j.tics.2011.08.004)

[Monahan Z, Shewmaker F, Pandey UB, Stress granules in disease pathogenesis (2016)](https://doi.org/10.1016/j.tifs.2016.05.004)

[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 (2012)](https://doi.org/10.1523/JNEUROSCI.2540-12.2012)

[Suzuki H, Matsuoka M, FUS toxicity is rescued by nuclear importin α2 (2013)](https://doi.org/10.1016/j.neurobiolaging.2013.04.025)

[Lattante S, Rouleau GA, Kabashi E, TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary of current animal models and perspectives (2013)](https://doi.org/10.1186/1749-8104-8-7)

[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 (2012)](https://doi.org/10.1016/j.neurobiolaging.2012.11.015)

[Korobeynikov VA, Borodinov A, Burley J, Lyashkov A, Shuvalova L, Kaehler M, Isacson O, Gene therapy approaches for FUS-ALS (2022)](https://doi.org/10.1016/j.stem.2022.03.018)

[Chen Y, Cohen TJ, Aggregation of RNA-binding proteins in ALS/FTD (2021)](https://doi.org/10.1016/j.tcb.2021.02.007)

[Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC, Amyotrophic lateral sclerosis (2011)](https://doi.org/10.1016/S0140-6736(11)

[Liu Y, Zhou Q, Wang Y, C9orf72 and FUS: shared genetic mechanisms in ALS/FTD (2016)](https://doi.org/10.1038/nrneurol.2016.160)

[Mitchell JC, McGough A, Wei J, Coleman VA, Farmer R, Woodman P, Gillingwater TH, Drosophila models of FUSopathies (2013)](https://doi.org/10.1016/j.nbd.2013.12.010)

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Related Entities

FUSPROTEIN

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slug	proteins-fus-protein
kg_node_id	FUSPROTEIN
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-92288eb6ef09
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-fus-protein'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

75%

Debates

0

Incoming

15

Outgoing

20

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

FUS Protein

FUS Protein

FUS Protein

Overview

FUS Protein

FUS Protein

Overview

Normal Physiological Function

RNA Processing

Transcriptional Regulation

Neuronal Functions

Pathogenic Mechanisms in ALS/FTD

Gain-of-Function

Aggregation

Selective Vulnerability

Mutations and Genotype-Phenotype Correlation

ALS-Causing Mutations

Genotype-Phenotype Relationships

Therapeutic Strategies

Gene Therapy Approaches

Small Molecule Approaches

Neuroprotective Strategies

Structure and Biochemistry

Interaction with Other ALS/FTD Proteins

Animal Models

Mouse Models

Cellular Models

Key Publications

Pathway & Interaction Diagram

External Links

See Also

Brain Atlas Resources

References

💬 Discussion