Fused in sarcoma protein (FUS) (FUS)

Fused in sarcoma (FUS) is a multifunctional RNA-binding protein that belongs to the FET family and is primarily localized in the nucleus. It plays a critical role in various cellular processes, including RNA splicing, mRNA transport, and the cellular response to DNA damage (UniProt P35637). In pathological states, particularly in certain forms of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD), FUS mislocalizes to the cytoplasm and forms insoluble aggregates. These aggregates are thought to cause neurodegeneration through a combination of losing its normal nuclear functions and gaining toxic properties in the cytoplasm, often by disrupting the dynamics of stress granules (PubMed: 21303895). Therapeutic efforts are currently centered on reducing the expression of FUS using antisense oligonucleotides (ASOs) like Jacifusen (ION363) to prevent or slow the accumulation of these toxic aggregates (ClinicalTrials.gov: NCT04768972). Research is also ongoing into small molecules that can modulate the protein's liquid-liquid phase separation to prevent the transition from a functional liquid state to a pathological solid aggregate.

Other names

TLSTranslocated in liposarcomahnRNP P2POMP7575 kDa DNA-pairing proteinFUS/TLSFUS protein aggregatesFUS inclusions

Antisense oligonucleotide-mediated reduction of FUS mRNA and protein levels; inhibition of liquid-liquid phase separation; enhancement of aggregate clearance.