PT  - JOURNAL ARTICLE
AU  - Urša Šušnjar
AU  - Neva Škrabar
AU  - Anna-Leigh Brown
AU  - Yasmine Abbassi
AU  - NYGC ALS Consortium
AU  - Hemali Phatnani
AU  - Andrea Cortese
AU  - Cristina Cereda
AU  - Enrico Bugiardini
AU  - Rosanna Cardani
AU  - Giovanni Meola
AU  - Michela Ripolone
AU  - Maurizio Moggio
AU  - Maurizio Romano
AU  - Maria Secrier
AU  - Pietro Fratta
AU  - Emanuele Buratti
TI  - Cell environment shapes TDP-43 function: implications in neuronal and muscle disease
AID  - 10.1101/2021.04.20.440589
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.20.440589
4099  - http://biorxiv.org/content/early/2021/04/23/2021.04.20.440589.short
4100  - http://biorxiv.org/content/early/2021/04/23/2021.04.20.440589.full
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.