Pathogenesis of FUS-associated ALS and FTD: Insights from Rodent Models

Overview

Journal Acta Neuropathol Commun

Publisher Biomed Central

Specialty Neurology

Date 2016 Sep 8

PMID 27600654

Citations 65

Authors

Matthew Nolan

Kevin Talbot

Olaf Ansorge

Affiliations

Soon will be listed here.

Abstract

Disruptions to genes linked to RNA processing and homeostasis are implicated in the pathogenesis of two pathologically related but clinically heterogeneous neurodegenerative diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mutations in the Fused-in-Sarcoma (FUS) gene encoding a 526 amino-acid RNA-binding protein are found in a small subset of ALS cases, but FUS mutations do not appear to be a direct cause of FTD. Structural and functional similarities between FUS and another ALS-related RNA-binding protein, TDP-43, highlight the potential importance of aberrant RNA processing in ALS/FTD, and this pathway is now a major focus of interest. Recently, several research groups have reported transgenic vertebrate models of FUSopathy, with varying results. Here, we discuss the evidence for FUS pathogenicity in ALS/FTD, review the experimental approaches used and phenotypic features of FUS rodent models reported to date, and outline their contribution to our understanding of pathogenic mechanisms. Further refinement of vertebrate models will likely aid our understanding of the role of FUS in both diseases.

Citing Articles

Investigation of the role of miRNA variants in neurodegenerative brain diseases.

Frydas A, Cacace R, van der Zee J, Van Broeckhoven C, Wauters E Front Genet. 2025; 16:1506169.

PMID: 40078479 PMC: 11897046. DOI: 10.3389/fgene.2025.1506169.

Direct and Indirect Protein Interactions Link FUS Aggregation to Histone Post-Translational Modification Dysregulation and Growth Suppression in an ALS/FTD Yeast Model.

Bennett S, Cobos S, Fisher R, Son E, Frederic R, Segal R J Fungi (Basel). 2025; 11(1).

PMID: 39852477 PMC: 11766905. DOI: 10.3390/jof11010058.

Amyotrophic lateral sclerosis represents corticomotoneuronal system failure.

Eisen A, Vucic S, Kiernan M Muscle Nerve. 2024; 71(4):499-511.

PMID: 39511939 PMC: 11887532. DOI: 10.1002/mus.28290.

A Review of Biomarkers of Amyotrophic Lateral Sclerosis: A Pathophysiologic Approach.

Alshehri R, Abuzinadah A, Alrawaili M, Alotaibi M, Alsufyani H, Alshanketi R Int J Mol Sci. 2024; 25(20).

PMID: 39456682 PMC: 11507293. DOI: 10.3390/ijms252010900.

hnRNPs: roles in neurodevelopment and implication for brain disorders.

Tilliole P, Fix S, Godin J Front Mol Neurosci. 2024; 17:1411639.

PMID: 39086926 PMC: 11288931. DOI: 10.3389/fnmol.2024.1411639.

References

Robinson H, Deykin A, Bronovitsky E, Ovchinnikov R, Ustyugov A, Shelkovnikova T . Early lethality and neuronal proteinopathy in mice expressing cytoplasm-targeted FUS that lacks the RNA recognition motif. Amyotroph Lateral Scler Frontotemporal Degener. 2015; 16(5-6):402-9. PMC: 4811325. DOI: 10.3109/21678421.2015.1040994. View

Huang C, Tong J, Bi F, Wu Q, Huang B, Zhou H . Entorhinal cortical neurons are the primary targets of FUS mislocalization and ubiquitin aggregation in FUS transgenic rats. Hum Mol Genet. 2012; 21(21):4602-14. PMC: 3471393. DOI: 10.1093/hmg/dds299. View

Scekic-Zahirovic J, Sendscheid O, El Oussini H, Jambeau M, Sun Y, Mersmann S . Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss. EMBO J. 2016; 35(10):1077-97. PMC: 4868956. DOI: 10.15252/embj.201592559. View

Kent L, Vizard T, Smith B, Topp S, Vance C, Gkazi A . Autosomal dominant inheritance of rapidly progressive amyotrophic lateral sclerosis due to a truncation mutation in the fused in sarcoma (FUS) gene. Amyotroph Lateral Scler Frontotemporal Degener. 2014; 15(7-8):557-62. DOI: 10.3109/21678421.2014.920033. View

Rodriguez de Rivera F, Rambold H, Diez-Tejedor E . Assessment of cognitive impairment in amyotrophic lateral sclerosis. J Neurol Sci. 2013; 337(1-2):1-2. DOI: 10.1016/j.jns.2013.11.030. View

Bentmann E, Neumann M, Tahirovic S, Rodde R, Dormann D, Haass C . Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43). J Biol Chem. 2012; 287(27):23079-94. PMC: 3391091. DOI: 10.1074/jbc.M111.328757. View

Bedford M, Clarke S . Protein arginine methylation in mammals: who, what, and why. Mol Cell. 2009; 33(1):1-13. PMC: 3372459. DOI: 10.1016/j.molcel.2008.12.013. View

Qiu H, Lee S, Shang Y, Wang W, Au K, Kamiya S . ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J Clin Invest. 2014; 124(3):981-99. PMC: 3938263. DOI: 10.1172/JCI72723. View

Tradewell M, Yu Z, Tibshirani M, Boulanger M, Durham H, Richard S . Arginine methylation by PRMT1 regulates nuclear-cytoplasmic localization and toxicity of FUS/TLS harbouring ALS-linked mutations. Hum Mol Genet. 2011; 21(1):136-49. DOI: 10.1093/hmg/ddr448. View

10.

Bury J, Highley J, Cooper-Knock J, Goodall E, Higginbottom A, McDermott C . Oligogenic inheritance of optineurin (OPTN) and C9ORF72 mutations in ALS highlights localisation of OPTN in the TDP-43-negative inclusions of C9ORF72-ALS. Neuropathology. 2015; 36(2):125-34. DOI: 10.1111/neup.12240. View

11.

Talbot K, Ansorge O . Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease. Hum Mol Genet. 2006; 15 Spec No 2:R182-7. DOI: 10.1093/hmg/ddl202. View

12.

Darovic S, Prpar Mihevc S, Zupunski V, Guncar G, Stalekar M, Lee Y . Phosphorylation of C-terminal tyrosine residue 526 in FUS impairs its nuclear import. J Cell Sci. 2015; 128(22):4151-9. DOI: 10.1242/jcs.176602. View

13.

Bosco D, Lemay N, Ko H, Zhou H, Burke C, Kwiatkowski Jr T . Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet. 2010; 19(21):4160-75. PMC: 2981014. DOI: 10.1093/hmg/ddq335. View

14.

Tateishi T, Hokonohara T, Yamasaki R, Miura S, Kikuchi H, Iwaki A . Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation. Acta Neuropathol. 2009; 119(3):355-64. DOI: 10.1007/s00401-009-0621-1. View

15.

Suarez-Calvet M, Neumann M, Arzberger T, Abou-Ajram C, Funk E, Hartmann H . Monomethylated and unmethylated FUS exhibit increased binding to Transportin and distinguish FTLD-FUS from ALS-FUS. Acta Neuropathol. 2016; 131(4):587-604. DOI: 10.1007/s00401-016-1544-2. View

16.

Rademakers R, Stewart H, DeJesus-Hernandez M, Krieger C, Graff-Radford N, Fabros M . Fus gene mutations in familial and sporadic amyotrophic lateral sclerosis. Muscle Nerve. 2010; 42(2):170-6. PMC: 2969843. DOI: 10.1002/mus.21665. View

17.

Huang C, Zhou H, Tong J, Chen H, Liu Y, Wang D . FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet. 2011; 7(3):e1002011. PMC: 3048370. DOI: 10.1371/journal.pgen.1002011. View

18.

Sephton C, Tang A, Kulkarni A, West J, Brooks M, Stubblefield J . Activity-dependent FUS dysregulation disrupts synaptic homeostasis. Proc Natl Acad Sci U S A. 2014; 111(44):E4769-78. PMC: 4226112. DOI: 10.1073/pnas.1406162111. View

19.

Yokota O, Tsuchiya K, Terada S, Ishizu H, Uchikado H, Ikeda M . Basophilic inclusion body disease and neuronal intermediate filament inclusion disease: a comparative clinicopathological study. Acta Neuropathol. 2007; 115(5):561-75. DOI: 10.1007/s00401-007-0329-z. View

20.

Beghi E, Chio A, Couratier P, Esteban J, Hardiman O, Logroscino G . The epidemiology and treatment of ALS: focus on the heterogeneity of the disease and critical appraisal of therapeutic trials. Amyotroph Lateral Scler. 2010; 12(1):1-10. PMC: 3513399. DOI: 10.3109/17482968.2010.502940. View