FUS-Targeting Therapies for Amyotrophic Lateral Sclerosis is a therapeutic approach or intervention being investigated for neurodegenerative diseases. This page reviews the scientific rationale, preclinical and clinical evidence, dosing considerations, and current status of research.
Fused in Sarcoma (FUS) is an RNA-binding protein implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)[1]. Mutations in the FUS gene (also known as TLS - Translocated in Sarcoma) account for approximately 5-10% of familial ALS cases and are associated with aggressive, early-onset disease phenotypes[2]. This page covers FUS biology, its role in ALS pathogenesis, and emerging therapeutic strategies targeting this pathway.
FUS (Fused in Sarcoma) is a 526-amino acid protein belonging to the FET (FUS, EWSR1, TAF15) family of RNA-binding proteins[1:1]. The protein contains multiple functional domains:
FUS participates in multiple essential cellular processes:
Pathogenic FUS mutations were first identified in ALS in 2009[2:1]. Over 50 mutations have been described, predominantly clustering in the C-terminal nuclear localization signal (NLS) region:
FUS normally localizes to stress granules under cellular stress. ALS-associated mutations lead to:
FUS mutations disrupt normal RNA processing:
The low-complexity domain of FUS undergoes liquid-liquid phase separation (LLPS), which is disrupted by ALS mutations:
FUS-associated ALS presents distinct clinical features:
ASOs targeting FUS mRNA are in development:
FUS-associated ALS represents a distinct and aggressive subtype of motor neuron disease with unique pathogenesis centered on RNA metabolism and phase separation biology. While no FUS-specific therapies are currently approved, multiple approaches including ASOs, small molecules, and protein clearance enhancers are in development. Early genetic diagnosis and emerging clinical trials offer hope for patients with this challenging condition.
Lagier-Tourenne C et al. FUS and ALS: From gene biology to therapeutic targets. Nature. 2010. ↩︎ ↩︎
Kwiatkowski TJ Jr et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science. 2009. ↩︎ ↩︎ ↩︎
Kato M et al. Cellular response to phase separation and stress. Cell. 2012. ↩︎
Lerga A et al. RNA-binding properties and purification of human FUS. Biochemistry. 2001. ↩︎
Dormann D et al. ALS-associated FUS mutations disrupt nuclear import. The EMBO Journal. 2010. ↩︎
King OD et al. The prion-like properties of ALS-associated proteins. Cell. 2012. ↩︎
Vance C et al. Mutations in FUS cause familial ALS. Science. 2009. ↩︎
Britton S et al. FUS is recruited to DNA damage sites. Proceedings of the National Academy of Sciences. 2014. ↩︎
Li YR et al. Stress granules in neurodegeneration. Nature Reviews Neurology. 2013. ↩︎
Sephton CF et al. FUS in synaptic function and disease. Brain Research. 2012. ↩︎
Chio A et al. FUS mutations in ALS: Phenotypic heterogeneity. Neurology. 2012. ↩︎
Belzil VV et al. FUS mutations in ALS: Clinical features and prognosis. Neurology. 2012. ↩︎
Conte A et al. FUS R514S mutation: Clinical heterogeneity. Neurology. 2012. ↩︎
Dormann D et al. Stress granule pathology in FUS-ALS. The EMBO Journal. 2010. ↩︎
Bentmann E et al. FUS pathology in ALS and FTD. Acta Neuropathologica. 2012. ↩︎
Kim HJ et al. FUS and translational control. Cell. 2012. ↩︎
Zhou Y et al. Splicing defects in FUS-ALS. Cell Reports. 2014. ↩︎
Deng J et al. FUS and mitochondrial dysfunction in ALS. Human Molecular Genetics. 2015. ↩︎
Locatelli F et al. FUS and axonal transport defects. Journal of Cell Biology. 2013. ↩︎
Murakami T et al. ALS mutations in FUS drive phase separation. Neuron. 2015. ↩︎
Patel A et al. A liquid-to-solid phase transition in FUS. Cell. 2015. ↩︎
Nonaka T et al. Prion-like propagation of FUS aggregates. Acta Neuropathologica. 2015. ↩︎
Rademakers R et al. FUS-ALS: Age of onset and progression. Neurology. 2011. ↩︎
Ticozzi N et al. Prognosis in FUS-ALS. Journal of Neurology, Neurosurgery & Psychiatry. 2011. ↩︎
Baek W et al. Bulbar onset in FUS-ALS. Journal of Clinical Neurology. 2011. ↩︎
Lattante S et al. Cognitive impairment in FUS-ALS. Brain. 2013. ↩︎
Van Langenhove T et al. FUS mutations in FTD. Brain. 2012. ↩︎
Tan RH et al. ALS-FTD spectrum and FUS. Nature Reviews Neurology. 2016. ↩︎
Bortone M et al. Antisense oligonucleotides for FUS-ALS. Methods in Molecular Biology. 2019. ↩︎
Korobeynikov VA et al. Antisense silencing of mutant FUS. Proceedings of the National Academy of Sciences. 2016. ↩︎
Bhattacharya T et al. FUS-ALS clinical trials status. Current Treatment Options in Neurology. 2022. ↩︎
Schoch KM et al. RNAi approaches for FUS-ALS. Neurobiology of Disease. 2016. ↩︎
Xia X et al. Delivery challenges for ALS therapeutics. Molecular Therapy. 2015. ↩︎
Kim HJ et al. Phase separation modulators for FUS. Cell. 2019. ↩︎
Wheeler RJ et al. Small molecules targeting phase separation. Nature Chemical Biology. 2019. ↩︎
Zhang P et al. Phase separation modulators in preclinical development. Trends in Pharmacological Sciences. 2020. ↩︎
Jaiswal MK. Riluzole and edaravone in FUS-ALS. Journal of Neurology. 2019. ↩︎
Orsini M et al. CoQ10 in ALS: Rationale and trials. Neurodegenerative Diseases. 2011. ↩︎
Paganoni S et al. Relyvrio (AMX0035) in ALS. Muscle & Nerve. 2020. ↩︎
Chen L et al. Rapamycin and autophagy enhancement. Autophagy. 2013. ↩︎
Li Y et al. Trehalose enhances FUS clearance. Cell Death & Disease. 2014. ↩︎
Tashiro Y et al. Proteasome activation in ALS. Human Molecular Genetics. 2012. ↩︎
Bensimon G et al. Riluzole in ALS: Clinical trials. The Lancet. 1994. ↩︎
Takei K et al. Edaravone in ALS: Clinical efficacy. Neurology and Clinical Neuroscience. 2017. ↩︎
Chio A et al. Multidisciplinary care in ALS. Nature Reviews Neurology. 2012. ↩︎
Strong MJ et al. Genetic testing in ALS. Lancet Neurology. 2017. ↩︎
Benatar M et al. Genetic counseling in ALS. Neurology. 2017. ↩︎
Lu CH et al. Neurofilament light chain as biomarker in ALS. Neurology. 2015. ↩︎
Feneberg E et al. CSF FUS levels in ALS. Annals of Clinical and Translational Neurology. 2017. ↩︎
Agosta F et al. MRI in ALS: Current status. Lancet Neurology. 2011. ↩︎
Van Weehaeghe D et al. PET in ALS: Neuroinflammation. European Journal of Nuclear Medicine and Molecular Imaging. 2019. ↩︎
Sarchielli C et al. FUS-ALS clinical trial outlook. Expert Opinion on Investigational Drugs. 2022. ↩︎
Benatar M et al. NfL as endpoint in ALS trials. Lancet Neurology. 2018. ↩︎
Chio A et al. ALS natural history studies. Lancet Neurology. 2015. ↩︎
Gaj T et al. CRISPR editing for ALS. Nature Reviews Neurology. 2017. ↩︎
Sareen D et al. iPSC models of FUS-ALS. Cell Stem Cell. 2013. ↩︎
Ding Z et al. PPI inhibitors for FUS aggregation. Journal of Medicinal Chemistry. 2020. ↩︎