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

Šušnjar, Urša, Škrabar, Neva, Brown, Anna-Leigh, Abbassi, Yasmine, Phatnani, Hemali, NYGC ALS Consortium, , Cortese, Andrea, Cereda, Cristina, Bugiardini, Enrico, Cardani, Rosanna, Meola, Giovanni, Ripolone, Michela, Moggio, Maurizio, Romano, Maurizio, Secrier, Maria, Fratta, Pietro, Buratti, Emanuele (April 2022) Cell environment shapes TDP-43 function with implications in neuronal and muscle disease. Communications Biology, 5 (1). p. 314. ISSN 2399-3642

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URL: https://www.ncbi.nlm.nih.gov/pubmed/35383280
DOI: 10.1038/s42003-022-03253-8

Abstract

TDP-43 (TAR DNA-binding protein 43) aggregation and redistribution are recognised as a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. As TDP-43 inclusions have recently been described in the muscle of inclusion body myositis patients, this highlights the need to understand the role of TDP-43 beyond the central nervous system. Using RNA-seq, we directly compare TDP-43-mediated RNA processing in muscle (C2C12) and neuronal (NSC34) mouse cells. TDP-43 displays a cell-type-characteristic behaviour targeting unique transcripts in each cell-type, which is due to characteristic expression of RNA-binding proteins, that influence TDP-43's performance and define cell-type specific splicing. Among splicing events commonly dysregulated in both cell lines, we identify some that are TDP-43-dependent also in human cells. Inclusion levels of these alternative exons are altered in tissues of patients suffering from FTLD and IBM. We therefore propose that TDP-43 dysfunction contributes to disease development either in a common or a tissue-specific manner.

Item Type: Paper
Subjects: diseases & disorders > nervous system diseases and disorders > amyotrophic lateral sclerosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > DNA binding protein
diseases & disorders > nervous system diseases and disorders > frontotemporal dementia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing
CSHL Authors:
Communities: CSHL labs > Hammell M. lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 5 April 2022
Date Deposited: 08 Jun 2022 20:03
Last Modified: 08 Jun 2022 20:03
PMCID: PMC8983780
URI: https://repository.cshl.edu/id/eprint/40655

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