The cleavage pattern of TDP-43 determines its rate of clearance and cytotoxicity

Quan Li, Moe Yokoshi, Hitomi Okada and Yukio Kawahara ()
Additional contact information
Quan Li: Graduate School of Medicine, Osaka University
Moe Yokoshi: Graduate School of Medicine, Osaka University
Hitomi Okada: Graduate School of Medicine, Osaka University
Yukio Kawahara: Graduate School of Medicine, Osaka University

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: Abstract TAR DNA-binding protein of 43 kDa (TDP-43) and its C-terminal fragment of 25 kDa (CTF25) play critical roles in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Although the overexpression of TDP-43 in cultured cells and animals results in the production of CTF25, the cleavage site that generates CTF25 and biological significance of the cleavage remain undetermined. Here we identify Asp174 as a cleavage site for CTF25. TDP-43 is cleaved initially after Asp174, which activates caspase-3/7 to accelerate TDP-43 fragmentation. Consequently, blockage of this cleavage results in a severe delay in TDP-43 clearance and prolonged necrotic cell death. We further show that the endoplasmic reticulum membrane-bound caspase-4 is the enzyme responsible for the cleavage after Asp174 and inhibition of caspase-4 activity slows TDP-43 fragmentation and reduces cell viability. These findings suggest that caspase-4-mediated cleavage after Asp174 is an initiator of TDP-43 clearance, which is required to avoid cell death induced by overexpressed TDP-43.

Date: 2015
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms7183 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7183

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms7183

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().