FUS
FUS is a gene associated with familial ALS, particularly in cases with early onset and aggressive progression. It belongs to a broader group of RNA-binding proteins that have emerged as central players in ALS biology, highlighting RNA regulation as a key vulnerability in motor neurons.
Normal function
FUS encodes a multifunctional RNA-binding protein that operates primarily in the nucleus, where it participates in RNA splicing, transport, and transcriptional regulation. It also contributes to DNA damage repair. Through these roles, FUS helps maintain proper gene expression and cellular integrity, particularly in neurons with high transcriptional and metabolic demands.
Mutation and effect
Disease-associated mutations often disrupt signals telling FUS to move to the neucleus, causing it to accumulate in the cytoplasm instead. This results in a dual problem: loss of normal nuclear function where, because of the lack of RNA processing, proteins are made incorrectly, and gain of toxic properties in the cytoplasm where FUS can form aggregates.
FUS pathology is driven by RNA dysregulation, abnormal phase separation, and stress granule dysfunction. In the cytoplasm, mutant FUS can become trapped in stress granules (temporary RNA-protein assemblies that form during cellular stress), altering their dynamics and persistence. This disrupts RNA processing and protein synthesis, contributing to cellular stress and impaired neuronal function.
Implications for treatment
FUS-associated ALS tends to present at a younger age and progress more rapidly than typical ALS. It often lacks classic TDP-43 pathology, indicating a distinct molecular subtype of disease driven by RNA-binding protein dysfunction rather than the more common TDP-43 pathway.
Therapeutic strategies aim to restore proper RNA regulation, prevent cytoplasmic aggregation, or correct protein localization, but these approaches are still largely experimental. The challenge is targeting toxic effects without disrupting the essential normal functions of FUS.
Research focus
Research on FUS is focused on how RNA-binding proteins become toxic when they mislocalize from the nucleus to the cytoplasm. A central question is how FUS mutations disrupt nuclear import, promote cytoplasmic aggregation, and alter the behavior of stress granules. Researchers are also exploring whether therapies can restore nuclear localization, reduce aggregation-prone FUS, or correct downstream RNA-processing defects. Because FUS-associated ALS is often early-onset and aggressive, there is strong interest in developing faster and more targeted therapeutic strategies.
Sources
- Moens, T. G., et al. (2025). Amyotrophic lateral sclerosis caused by FUS mutations.
- Xiao, X., et al. (2024). FUS gene mutation in amyotrophic lateral sclerosis.
- Mariani, D., et al. (2024). ALS-associated FUS mutation reshapes the RNA and protein composition of cytoplasmic ribonucleoprotein granules.
- Assoni, A. F., et al. (2023). Amyotrophic Lateral Sclerosis, FUS and Protein Synthesis Dysfunction.