From the Guidelines
Fused in sarcoma (FUS) protein is a critical RNA-binding protein associated with neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), where its mislocalization and aggregation contribute to neuronal dysfunction and death. The FUS protein plays multiple roles in cellular function, primarily shuttling between the nucleus and cytoplasm, regulating gene expression through involvement in transcription, RNA processing, and RNA transport 1. It contains several functional domains, including an RNA recognition motif and a nuclear localization signal, which enable its diverse functions. Mutations in the FUS gene are strongly associated with ALS and FTD, where the protein often mislocalizes from the nucleus to the cytoplasm and forms pathological aggregates in affected neurons, disrupting normal RNA metabolism and contributing to neuronal dysfunction and death 1.
Key Points
- FUS protein is essential for RNA binding and regulation of gene expression
- Mutations in the FUS gene are associated with neurodegenerative diseases, particularly ALS and FTD
- Mislocalization and aggregation of FUS protein contribute to neuronal dysfunction and death
- Understanding FUS protein function and dysfunction is crucial for developing therapeutic approaches for ALS, FTD, and other neurodegenerative disorders
The most recent study on the topic, published in 2023, highlights the importance of standardized ontologies in describing and annotating results of model experiments, relating these terms across species, and enabling downstream meta-analyses and providing extensive labelled training datasets for more complex machine learning models 1. However, this study does not directly address the FUS protein. In contrast, the 2018 study provides more detailed information on the FUS protein and its association with neurodegenerative diseases, particularly ALS and FTD 1.
Clinical Implications
- Early diagnosis and treatment of ALS and FTD are crucial to prevent neuronal dysfunction and death
- Understanding FUS protein function and dysfunction can inform the development of therapeutic approaches for ALS, FTD, and other neurodegenerative disorders
- Standardized ontologies can facilitate the translation of insights from models of neurodegeneration to clinical practice.
Overall, the FUS protein plays a critical role in neurodegenerative diseases, and understanding its function and dysfunction is essential for developing effective therapeutic approaches.
From the Research
Fused in Sarcoma Protein Overview
- Fused in sarcoma (FUS) is a DNA/RNA binding protein involved in RNA metabolism and DNA repair 2.
- FUS is associated with various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and polyglutamine diseases 2, 3, 4, 5, 6.
FUS and Neurodegenerative Diseases
- Mutations in FUS lead to its mislocalization from the nucleus to the cytosol and formation of pathogenic aggregates in neurodegenerative diseases 3, 6.
- FUS-positive neuronal cytoplasmic inclusions are found in patients with ALS and FTLD 2, 5.
- The fibrillar aggregation of FUS and its prion-like domains (PrLDs) are considered key factors in the pathology of these diseases 2.
FUS Self-Assembly and Aggregation
- FUS exhibits a nonfibrillar self-assembling phenomenon, known as liquid-liquid phase separation (LLPS) 2.
- Mutant FUS oligomers are extremely stable and resistant to treatment, which may contribute to ALS/FTLD pathogenesis 3.
- The increased oligomerization units of mutant FUS and their high stability may play a role in the formation of pathogenic aggregates 3.
FUS Interactions and Pathways
- FUS interacts with proteins involved in metabolic and protein degradation pathways, including VCP/p97, PSF, UBA 1, and 26S proteosome non-ATPase regulatory subunit 12 (PSMD12/Rpn5) 4.
- FUS accumulation leads to defective energy metabolism and protein degradation by directly interacting with key regulators in these pathways 4.
- FUS-mediated alternative splicing in the nervous system may contribute to the pathology of ALS and FTLD, with targets including ABLIM1, BRAF, EWSR1, MAPT, NRCAM, and NTNG1 5.