RT Journal Article
SR Electronic
T1 Cell environment shapes TDP-43 function: implications in neuronal and muscle disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.20.440589
DO 10.1101/2021.04.20.440589
A1 Urša Šušnjar
A1 Neva Škrabar
A1 Anna-Leigh Brown
A1 Yasmine Abbassi
A1 NYGC ALS Consortium
A1 Hemali Phatnani
A1 Andrea Cortese
A1 Cristina Cereda
A1 Enrico Bugiardini
A1 Rosanna Cardani
A1 Giovanni Meola
A1 Michela Ripolone
A1 Maurizio Moggio
A1 Maurizio Romano
A1 Maria Secrier
A1 Pietro Fratta
A1 Emanuele Buratti
YR 2021
UL http://biorxiv.org/content/early/2021/04/23/2021.04.20.440589.abstract
AB 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.