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

PDF 2022.susnjar.shapes.tdp43.pdf Available under License Creative Commons Attribution. Download (2MB)

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:	Hammell, Molly
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

Actions (login required)

Administrator's edit/view item