FUS, also known as Fused in Sarcoma, is an RNA-binding protein involved in RNA metabolism and DNA repair. It can undergo liquid-liquid phase separation (LLPS), forming dynamic liquid-like compartments that are crucial for its physiological role [1,2]. Mutations in FUS are associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [3,4].

In ALS-FUS mouse models, a series of FUS knock-in lines expressing ALS-associated mutant FUSP525L and FUSΔEX14 proteins showed progressive, age-dependent motor neuron loss due to a dose-dependent gain of toxic function. The insolubility of FUS and related RNA-binding proteins was observed. Treatment with the non-allele-specific FUS antisense oligonucleotide ION363 in these mice efficiently silenced Fus, reduced FUS protein levels in the brain and spinal cord, and delayed motor neuron degeneration. In a patient with ALS and a FUSP525L mutation, ION363 also lowered wild-type and mutant FUS levels in the central nervous system and reduced the burden of FUS aggregates [5].

In conclusion, FUS is essential for RNA metabolism and DNA repair, with its abnormal phase transitions and mutations linked to neurodegenerative diseases. The study of FUS in mouse models, especially through gene-targeted approaches like knock-in models, has provided valuable insights into the disease mechanisms of ALS and FTD, suggesting FUS silencing as a potential therapeutic strategy [5].

References:

1. Patel, Avinash, Lee, Hyun O, Jawerth, Louise, Hyman, Anthony A, Alberti, Simon. . A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. In Cell, 162, 1066-77. doi:10.1016/j.cell.2015.07.047. https://pubmed.ncbi.nlm.nih.gov/26317470/

2. Levone, Brunno R, Lenzken, Silvia C, Antonaci, Marco, Ruepp, Marc-David, Barabino, Silvia M L. . FUS-dependent liquid-liquid phase separation is important for DNA repair initiation. In The Journal of cell biology, 220, . doi:10.1083/jcb.202008030. https://pubmed.ncbi.nlm.nih.gov/33704371/

3. Xiao, Xin, Li, Min, Ye, Zhi, Wei, Jun, Zha, Yunhong. 2024. FUS gene mutation in amyotrophic lateral sclerosis: a new case report and systematic review. In Amyotrophic lateral sclerosis & frontotemporal degeneration, 25, 1-15. doi:10.1080/21678421.2023.2272170. https://pubmed.ncbi.nlm.nih.gov/37926865/

4. Mackenzie, Ian Ra, Rademakers, Rosa, Neumann, Manuela. . TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. In The Lancet. Neurology, 9, 995-1007. doi:10.1016/S1474-4422(10)70195-2. https://pubmed.ncbi.nlm.nih.gov/20864052/

5. Korobeynikov, Vladislav A, Lyashchenko, Alexander K, Blanco-Redondo, Beatriz, Jafar-Nejad, Paymaan, Shneider, Neil A. 2022. Antisense oligonucleotide silencing of FUS expression as a therapeutic approach in amyotrophic lateral sclerosis. In Nature medicine, 28, 104-116. doi:10.1038/s41591-021-01615-z. https://pubmed.ncbi.nlm.nih.gov/35075293/