Reduced cellular Ca(2+) availability enhances TDP-43 cleavage by apoptotic caspases.

Abstract

Accumulation of transactive response DNA binding protein (TDP-43) fragments in motor neurons is a post mortem hallmark of different neurodegenerative diseases. TDP-43 fragments are the products of the apoptotic caspases-3 and -7. Either excessive or insufficient cellular Ca(2+) availability is associated with activation of apoptotic caspases. However, as far as we know, it is not described whether activation of caspases, due to restricted intracellular Ca(2+), affects TDP-43 cleavage. Here we show that in various cell lineages with restricted Ca(2+) availability, TDP-43 is initially cleaved by caspases-3 and -7 and then, also by caspases-6 and -8 once activated by caspase-3. Furthermore, we disclose the existence of a TDP-43 caspase-mediated fragment of 15kDa, in addition to the well-known fragments of 35 and 25kDa. Interestingly, with respect to the other two fragments this novel fragment is the major product of caspase activity on murine TDP-43 whereas in human cell lines the opposite occurs. This outcome should be considered when murine models are used to investigate TDP-43 proteinopathies.

• Authors: Giovanni De Marco, Annarosa Lomartire, Giorgia Mandili, Elisa Lupino, Barbara Buccinnà, Cristina Ramondetti, Cristina Moglia, Francesco Novelli, Marco Piccinini, Michael Mostert, Maria Teresa Rinaudo, Adriano Chiò, Andrea Calvo
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1843 Issue 4 Pg. 725-34 (Apr 2014) ISSN: 0006-3002 [Print] Netherlands
• PMID: 24440855 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• DNA-Binding Proteins
• Caspases
• Calcium

Topics

• Animals
• Apoptosis (genetics)
• Calcium (metabolism)
• Caspases (metabolism)
• DNA-Binding Proteins (chemistry, genetics, metabolism)
• Gene Expression Regulation
• HeLa Cells
• Humans
• Mice