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Cell environment shapes TDP-43 function: implications in neuronal and muscle disease

Urša Šušnjar, Neva Škrabar, View ORCID ProfileAnna-Leigh Brown, Yasmine Abbassi, NYGC ALS Consortium, Hemali Phatnani, Andrea Cortese, View ORCID ProfileCristina Cereda, View ORCID ProfileEnrico Bugiardini, Rosanna Cardani, View ORCID ProfileGiovanni Meola, Michela Ripolone, Maurizio Moggio, View ORCID ProfileMaurizio Romano, Maria Secrier, Pietro Fratta, View ORCID ProfileEmanuele Buratti
doi: https://doi.org/10.1101/2021.04.20.440589
Urša Šušnjar
1Molecular Pathology Lab, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
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Neva Škrabar
2Tumour Virology Lab, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
3Generatio GmbH, Center for Animal, Genetics, Tübingen, Germany
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Anna-Leigh Brown
4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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Yasmine Abbassi
1Molecular Pathology Lab, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
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Hemali Phatnani
6Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, USA
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Andrea Cortese
4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
7Department of Brain and Behaviour Sciences, University of Pavia, Pavia, Italy
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Cristina Cereda
8Genomic and post-Genomic Unit, IRCCS Mondino Foundation, Pavia, Italy
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Enrico Bugiardini
4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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  • ORCID record for Enrico Bugiardini
Rosanna Cardani
9BioCor Biobank, UOC SMEL-1 of Clinical Pathology, IRCCS-Policlinico San Donato, San Donato Milanese, Italy
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Giovanni Meola
10Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
11Department of Neurorehabilitation Sciences, Casa di Cura del Policlinico, Milan, Italy
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Michela Ripolone
12Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Maurizio Moggio
12Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
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Maurizio Romano
13Department of Life Sciences, University of Trieste, Trieste, Italy
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Maria Secrier
14UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, UK
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Pietro Fratta
4Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
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Emanuele Buratti
1Molecular Pathology Lab, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
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  • For correspondence: buratti@icgeb.org
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ABSTRACT

TDP-43 aggregation and redistribution have been recognised as a hallmark of amyotrophic lateral sclerosis, frontotemporal dementia and other neurological disorders. While TDP-43 has been studied extensively in neuronal tissues, TDP-43 inclusions have also been described in the muscle of inclusion body myositis patients, highlighting the need to understand the role of TDP-43 beyond the central nervous system. Using RNA-seq we performed the first direct comparison of TDP-43-mediated transcription and alternative splicing in muscle (C2C12) and neuronal (NSC34) mouse cells. Our results clearly show that TDP-43 displays a tissue-characteristic behaviour targeting unique transcripts in each cell type. This is not due to variable transcript abundance but rather due to cell-specific expression of RNA-binding proteins, which influences TDP-43 performance. Among splicing events commonly dysregulated in both cell lines, we identified some that are TDP-43-dependent also in human cells and show that inclusion levels of these alternative exons appear to be differentially altered in affected tissues of FTLD and IBM patients. We therefore propose that TDP-43 dysfunction, reflected in aberrant splicing, contributes to disease development but it does so in a tissue- and disease-specific manner.

Footnotes

  • ↵5 A complete list of the NYGC ALS Consortium members is found in the Supplemental Acknowledgments file

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 23, 2021.
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Cell environment shapes TDP-43 function: implications in neuronal and muscle disease
Urša Šušnjar, Neva Škrabar, Anna-Leigh Brown, Yasmine Abbassi, NYGC ALS Consortium, Hemali Phatnani, Andrea Cortese, Cristina Cereda, Enrico Bugiardini, Rosanna Cardani, Giovanni Meola, Michela Ripolone, Maurizio Moggio, Maurizio Romano, Maria Secrier, Pietro Fratta, Emanuele Buratti
bioRxiv 2021.04.20.440589; doi: https://doi.org/10.1101/2021.04.20.440589
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Cell environment shapes TDP-43 function: implications in neuronal and muscle disease
Urša Šušnjar, Neva Škrabar, Anna-Leigh Brown, Yasmine Abbassi, NYGC ALS Consortium, Hemali Phatnani, Andrea Cortese, Cristina Cereda, Enrico Bugiardini, Rosanna Cardani, Giovanni Meola, Michela Ripolone, Maurizio Moggio, Maurizio Romano, Maria Secrier, Pietro Fratta, Emanuele Buratti
bioRxiv 2021.04.20.440589; doi: https://doi.org/10.1101/2021.04.20.440589

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