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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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: bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
diseases & disorders > mental disorders > delirium dementia cognitive disorders
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > mental disorders
diseases & disorders > nervous system diseases and disorders
diseases & disorders > nervous system diseases and disorders > amyotrophic lateral sclerosis
organism description > animal
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
organism description > animal > mammal
organism description > animal > mammal > rodent > mouse
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing
organism description > animal > mammal > rodent
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: 17 Jan 2024 19:43
PMCID: PMC8983780
URI: https://repository.cshl.edu/id/eprint/40655

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