Šušnjar, Urša;
Škrabar, Neva;
Brown, Anna-Leigh;
Abbassi, Yasmine;
Phatnani, Hemali;
NYGC ALS Consortium, .;
Cortese, Andrea;
... Buratti, Emanuele; + view all
(2022)
Cell environment shapes TDP-43 function with implications in neuronal and muscle disease.
Communications Biology
, 5
, Article 314. 10.1038/s42003-022-03253-8.
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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.
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