Fused in Sarcoma is a protein encoded by the [C9orf72](/genes/c9orf72) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Fused in Sarcoma (FUS) is a DNA/RNA-binding protein that plays critical roles in RNA splicing, transcription, and DNA repair [@deng2009][@lagiertourenne2010]. Mutations in the FUS gene are causally linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [@deng2009].
Gene Overview
Structure
The FUS protein contains multiple functional domains:
N-terminal Low-Complexity Domain - Prone to liquid-liquid phase separation, forms stress granules [@auto_37399327]
RNA Recognition Motif (RRM) - Binds RNA molecules
Zinc Finger Domain - DNA binding capability
C-terminal Proline-rich Region - Protein-protein interactions
Fused in Sarcoma is a protein encoded by the [C9orf72](/genes/c9orf72) gene. This page describes its structure, normal nervous system function, role in neurodegenerative disease, and potential as a therapeutic target.
Fused in Sarcoma (FUS) is a DNA/RNA-binding protein that plays critical roles in RNA splicing, transcription, and DNA repair [@deng2009][@lagiertourenne2010]. Mutations in the FUS gene are causally linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [@deng2009].
Gene Overview
Structure
The FUS protein contains multiple functional domains:
N-terminal Low-Complexity Domain - Prone to liquid-liquid phase separation, forms stress granules [@auto_37399327]
RNA Recognition Motif (RRM) - Binds RNA molecules
Zinc Finger Domain - DNA binding capability
C-terminal Proline-rich Region - Protein-protein interactions
Pathogenic Mechanisms
Phase Separation and Stress Granules
FUS participates in stress granule formation through its low-complexity domain [@auto_37399327]. In disease:
Mutations in FUS lead to aberrant phase separation [@shan2019]
Dysregulated stress granule dynamics cause toxic aggregation [@shan2019][@auto_35297101]
Impaired RNA metabolism due to sequestered RNA-binding proteins
Nuclear Import Defects
FUS mutations impair nuclear import via importin-α/β pathway [@deng2009]
Cytoplasmic FUS accumulation is a hallmark of FUS-ALS [@deng2009]
Nuclear loss-of-function disrupts RNA processing
DNA Damage Response
FUS is involved in DNA repair mechanisms [@auto_32987654]:
Associates with DNA double-strand break sites
Facilitates homologous recombination
Loss of DNA repair function contributes to neurodegeneration
Disease Associations
Amyotrophic Lateral Sclerosis (ALS)
FUS mutations account for ~5% of familial ALS cases [@deng2009][@lagiertourenne2010]:
Onset typically earlier than SOD1/C9orf72 ALS (median age 40-50)
Predominant bulbar onset in some mutations
Rapid progression in certain variants
FUS-positive inclusions in motor neurons
Frontotemporal Dementia (FTD)
FUS pathology in ~10% of FTD cases [@taylor2016]
Often co-occurs with ALS [@lagiertourenne2010]
Behavioral variant FTD presentation [@taylor2016]
Language variant FTD (especially non-fluent variant)