Cell environment shapes TDP-43 function with implications in neuronal and muscle disease

The aetiology of the TDP-43 aggregation manifest itself in the muscle and neuronal cells. Here authors show cell-type characteristic functions of TDP43, reflected in aberrant splicing, likely contributing to disease development. 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.

Automated summary

This study investigates the role of TDP-43 in muscle and neuronal cells, and discovers the association between aberrant splicing of TDP-43 and disease development. Using RNA-seq technology, the authors compare the differences in TDP-43-mediated RNA processing between muscle and neuronal cells. The results demonstrate the cell-type characteristic behavior of TDP-43, which is influenced by the expression of RNA-binding proteins and defines cell-type specific splicing. Some splicing events identified in both cell lines are also TDP-43-dependent in human cells, and the inclusion levels of alternative exons are altered in patients with FTLD and IBM.