FUS (Fused in Sarcoma) proteinopathy is a critical pathological mechanism in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The FUS protein is an RNA-binding protein involved in RNA metabolism, transcription regulation, and DNA damage repair. Pathogenic mutations and cytoplasmic inclusions of FUS are found in approximately 5-10% of familial ALS cases and some FTD cases.
FUS proteinopathy involves the mislocalization of FUS protein from the nucleus to the cytoplasm, where it forms stress granules and eventually insoluble inclusions. This leads to loss of nuclear FUS function and gain of toxic cytoplasmic function. Key features include:
FUS (Fused in Sarcoma) is a 526-amino acid protein encoded by the FUS gene on chromosome 16. It contains multiple functional domains:
Normal FUS functions:
Over 50 ALS-associated mutations in FUS have been identified, primarily in the NLS region:
| Mutation | Location | Effect |
|---|---|---|
| R521C | NLS | Reduced nuclear import |
| R521G | NLS | Impaired nuclear localization |
| P525L | NLS | Severe mislocalization |
| R514G | NLS | Partial mislocalization |
| G507R | NLS | Partial mislocalization |
Most mutations are autosomal dominant with high penetrance.
The NLS mutations impair binding to transportin (karyopherin-β2), the nuclear import receptor:
This leads to:
FUS is recruited to stress granules (SGs) under cellular stress:
Stress granule components include:
FUS undergoes liquid-liquid phase separation (LLPS):
The R521C and P525L mutations accelerate phase separation.
FUS-positive inclusions are found in:
Inclusion types:
| Mutation | Inheritance | Onset | Phenotype |
|---|---|---|---|
| R521C | Autosomal dominant | ~40 years | Classic ALS |
| R521G | Autosomal dominant | ~45 years | ALS-FTD |
| P525L | Autosomal dominant | ~25 years | Early-onset ALS |
| R514S | Autosomal dominant | ~50 years | Classic ALS |
The study of Fus Proteinopathy Pathway In Als 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.
Dormann D, et al. ALS-associated FUS mutations result in compromised nuclear import. EMBO J. 2010;29(16):2842-2857. PMID:20857542
Bentmann E, et al. Requirements for stress granule recruitment of FUS and TDP-43. Brain. 2012;135(Pt 9):2920-2931. PMID:22891160
Deng H, et al. FUS pathology: the new ALS paradigm. Neurobiol Aging. 2014;35(11):2482-2490. PMID:24944096
Shelkovnikova TA, et al. FUS pathology in ALS: the role of stress granules. Brain. 2013;136(Pt 4):1066-1076. PMID:23427321
Kwiatkowski TJ Jr, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009;323(5918):1205-1208. PMID:19251628
Vance C, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208-1211. PMID:19251627
Liu-Yesucevitz L, et al. ALS-linked FUS mutations alter stress granule dynamics. J Neurosci. 2010;30(38):12732-12744. PMID:20861310
Ito D, et al. ALS-associated FUS mutations induce stress granule formation. Mol Brain. 2011;4:32. PMID:21880132
Page created: 2026-03-06
Tags: FUS, ALS, FTD, proteinopathy, RNA-binding protein, stress granules
🔴 Low Confidence
| Dimension | Score |
|---|---|
| Supporting Studies | 8 references |
| Replication | 0% |
| Effect Sizes | 25% |
| Contradicting Evidence | 0% |
| Mechanistic Completeness | 75% |
Overall Confidence: 36%