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Low Level of Expression of C-Terminally Truncated Human FUS Causes Extensive Changes in the Spinal Cord Transcriptome of Asymptomatic Transgenic Mice

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Abstract

A number of mutations in a gene encoding RNA-binding protein FUS have been linked to the development of a familial form of amyotrophic lateral sclerosis known as FUS-ALS. C-terminal truncations of FUS by either nonsense or frameshift mutations lead to the development of FUS-ALS with a particularly early onset and fast progression. However, even in patients bearing these highly pathogenic mutations the function of motor neurons is not noticeably compromised for at least a couple of decades, suggesting that until cytoplasmic levels of FUS lacking its C-terminal nuclear localisation signal reaches a critical threshold, motor neurons are able to tolerate its permanent production. In order to identify how the nervous system responds to low levels of pathogenic variants of FUS we produced and characterised a mouse line, L-FUS[1–359], with a low neuronal expression level of a highly aggregation-prone and pathogenic form of C-terminally truncated FUS. In contrast to mice that express substantially higher level of the same FUS variant and develop severe early onset motor neuron pathology, L-FUS[1–359] mice do not develop any clinical or histopathological signs of motor neuron deficiency even at old age. Nevertheless, we detected substantial changes in the spinal cord transcriptome of these mice compared to their wild type littermates. We suggest that at least some of these changes reflect activation of cellular mechanisms compensating for the potentially damaging effect of pathogenic FUS production. Further studies of these mechanism might reveal effective targets for therapy of FUS-ALS and possibly, other forms of ALS.

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Data Availability

Data generated during this study are included in this published article and its Supplementary Information files and the RNA sequencing data were deposited in Gene Expression Omnibus (GEO) under the number GSE130604.

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Acknowledgements

We are thankful to Angela Marchbank and Georgina Smethurst from the Cardiff School of Biosciences Genomics Research Hub for help with RNA sequencing, Don Cleveland for sharing with us human FUS specific antibody, and Harri Harrison for critical reading of the manuscript. This study was supported by Russian Science Foundation Projects RScF#18–15-00357 (phenotyping of L-FUS mice), RScF#17-75-20-249, (producing the L-FUS mice) and the Motor Neuron Disease Association research grant (Buchman/Apr13/6096). Bioresource Collection of IPAC RAS (No. 0090-2017-0016) and Core Facility IGB RAS were used to maintain transgenic mice and test their behaviour using equipment of the Centre for Collective Use IPAC RAS. RNA sequencing analysis was supported by Russian President Foundation grant MК-3316.2019.4. Differential expression analysis was performed using the equipment of the Engelhardt Institute of Molecular Biology RAS “Genome” center (https://www.eimb.ru/rus/ckp/ccu_genome_c.php).

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Authors and Affiliations

  1. Institute of Physiologically Active Compounds, Russian Academy of Sciences, 1 Severnyj Proezd, Chernogolovka, Russian Federation

    Ekaterina A. Lysikova, Kirill D. Chaprov, Michail S. Kukharsky, Aleksey Ustyugov, Sergey O. Bachurin, Natalia Ninkina & Vladimir L. Buchman

  2. School of Biosciences, Cardiff University, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX, UK

    Ekaterina A. Lysikova, Natalia Ninkina & Vladimir L. Buchman

  3. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilova str., 32, Moscow, Russian Federation, 119991

    Sergei Funikov & Alexander P. Rezvykh

  4. Moscow Institute of Physics and Technology, 9 Institutskiy Per., Dolgoprudny, Moscow Region, Russian Federation, 141701

    Alexander P. Rezvykh

  5. Pirogov Russian National Research Medical University, Ostrovitianova str 1, Moscow, Russian Federation

    Michail S. Kukharsky

  6. Institute of Gene Biology, Russian Academy of Sciences, Vavilova str., 34/5, Moscow, Russian Federation, 19334

    Alexey V. Deykin

  7. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK

    Ilya M. Flyamer & Shelagh Boyle

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  1. Ekaterina A. Lysikova
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Contributions

NN and VLB conceived the project, designed the study, carried out certain experiments, interpreted experimental data and wrote the manuscript. EAL acquired and analysed molecular biology and behaviour data, prepared figures and wrote drafts of manuscript sections. SF and APR performed bioinformatic analysis of RNAseq data, drafted results and prepared corresponding table and figures. KDC and MSK performed immunohistochemical and Western blot analyses. AU and AVD produced transgenic mice and generated survival data. IMF and SB defined chromosomal localisation of transgenic cassettes in both hFUS[1–359] lines. SOB interpreted experimental data. All authors reviewed the manuscript.

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Correspondence to Ekaterina A. Lysikova.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (The Bioethics committee of Institute of Physiologically Active Compounds, Russian Academy of Sciences approval No. 20 dated 23.06.2017). All animal work was carried out in accordance with this approval and the Rules of Good Laboratory Practice in Russian Federation (2016).

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Lysikova, E.A., Funikov, S., Rezvykh, A.P. et al. Low Level of Expression of C-Terminally Truncated Human FUS Causes Extensive Changes in the Spinal Cord Transcriptome of Asymptomatic Transgenic Mice. Neurochem Res 45, 1168–1179 (2020). https://doi.org/10.1007/s11064-020-02999-z

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