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M6A reduction relieves FUS-associated ALS granules

Author

Listed:
  • Gaia Timoteo

    (Sapienza University of Rome)

  • Andrea Giuliani

    (Sapienza University of Rome)

  • Adriano Setti

    (Sapienza University of Rome)

  • Martina C. Biagi

    (Fondazione Istituto Italiano di Tecnologia (IIT))

  • Michela Lisi

    (Sapienza University of Rome)

  • Tiziana Santini

    (Sapienza University of Rome)

  • Alessia Grandioso

    (Sapienza University of Rome)

  • Davide Mariani

    (Center for Human Technologies@Istituto Italiano di Tecnologia (IIT))

  • Francesco Castagnetti

    (Center for Human Technologies@Istituto Italiano di Tecnologia (IIT))

  • Eleonora Perego

    (Center for Human Technologies@Istituto Italiano di Tecnologia (IIT))

  • Sabrina Zappone

    (Center for Human Technologies@Istituto Italiano di Tecnologia (IIT))

  • Serena Lattante

    (Università Cattolica del Sacro Cuore)

  • Mario Sabatelli

    (Università Cattolica del Sacro Cuore
    Fondazione Policlinico Universitario A. Gemelli IRCCS)

  • Dante Rotili

    (Sapienza University of Rome)

  • Giuseppe Vicidomini

    (Center for Human Technologies@Istituto Italiano di Tecnologia (IIT))

  • Irene Bozzoni

    (Sapienza University of Rome
    Fondazione Istituto Italiano di Tecnologia (IIT)
    Center for Human Technologies@Istituto Italiano di Tecnologia (IIT))

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA m6A content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after m6A downregulation. Notably, cells expressing mutant FUS were characterized by higher m6A levels suggesting a possible link between m6A homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.

Suggested Citation

  • Gaia Timoteo & Andrea Giuliani & Adriano Setti & Martina C. Biagi & Michela Lisi & Tiziana Santini & Alessia Grandioso & Davide Mariani & Francesco Castagnetti & Eleonora Perego & Sabrina Zappone & Se, 2024. "M6A reduction relieves FUS-associated ALS granules," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49416-5
    DOI: 10.1038/s41467-024-49416-5
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    References listed on IDEAS

    as
    1. Hao Song & Jiaxi Song & Ming Cheng & Meijuan Zheng & Tian Wang & Sha Tian & Richard A. Flavell & Shu Zhu & Hua-Bing Li & Chen Ding & Haiming Wei & Rui Sun & Hui Peng & Zhigang Tian, 2021. "METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Dario Dattilo & Gaia Di Timoteo & Adriano Setti & Andrea Giuliani & Giovanna Peruzzi & Manuel Beltran Nebot & Alvaro Centrón-Broco & Davide Mariani & Chiara Mozzetta & Irene Bozzoni, 2023. "The m6A reader YTHDC1 and the RNA helicase DDX5 control the production of rhabdomyosarcoma-enriched circRNAs," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Eleonora Perego & Sabrina Zappone & Francesco Castagnetti & Davide Mariani & Erika Vitiello & Jakob Rupert & Elsa Zacco & Gian Gaetano Tartaglia & Irene Bozzoni & Eli Slenders & Giuseppe Vicidomini, 2023. "Single-photon microscopy to study biomolecular condensates," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Eliza Yankova & Wesley Blackaby & Mark Albertella & Justyna Rak & Etienne Braekeleer & Georgia Tsagkogeorga & Ewa S. Pilka & Demetrios Aspris & Dan Leggate & Alan G. Hendrick & Natalie A. Webster & By, 2021. "Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia," Nature, Nature, vol. 593(7860), pages 597-601, May.
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