Fused in sarcoma protein aggregates (FUS)

Fused in sarcoma (FUS) is a multifunctional RNA-binding protein that normally shuttles between the nucleus and cytoplasm to regulate RNA processing, DNA repair, and gene expression (UniProt Consortium, 2024). In certain neurodegenerative conditions, FUS undergoes a pathological transition from a soluble state into insoluble cytoplasmic aggregates, a process often driven by mutations in its nuclear localization signal or prion-like domain (Lagier-Tourenne et al., 2010). These aggregates are a hallmark of specific subtypes of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD), where they lead to both a loss of normal nuclear function and a gain of cytoplasmic toxicity (Mackenzie et al., 2010). Therapeutic strategies currently focus on reducing total FUS levels using antisense oligonucleotides (ASOs), such as Jacifusen, to prevent the formation of these toxic species in patients with FUS mutations (Ionis Pharmaceuticals, 2021). Emerging research also explores small molecules designed to modulate the liquid-liquid phase separation (LLPS) of FUS to keep the protein in a functional, non-aggregated state (Naumann et al., 2018). Targeting FUS aggregates represents a precision medicine approach for rapidly progressive forms of motor neuron disease.

Other names

TLSTranslocated in liposarcomahnRNP P2POMP75FUS/TLSHeterogeneous nuclear ribonucleoprotein P2

Antisense oligonucleotide-mediated knockdown of FUS mRNA to reduce total protein levels and subsequent aggregation; small molecule modulation of liquid-liquid phase separation to prevent transition from liquid droplets to solid aggregates.