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.

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

DE MARCO, GIOVANNI;LOMARTIRE, ANNAROSA;MANDILI, GIORGIA;LUPINO, Elisa;BUCCINNA', Barbara;RAMONDETTI, Cristina;MOGLIA, CRISTINA;NOVELLI, Francesco;PICCININI, Marco;MOSTERT, Michael Martin;RINAUDO, Maria Teresa;CHIO', Adriano;CALVO, Andrea
2014-01-01

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.
1843
4
725
734
Apoptosis, Ca(2+) deprivation, Caspase, TDP-43 cleavage
G. De Marco; A. Lomartire; G. Mandili; E. Lupino; B. Buccinnà; C. Ramondetti; C. Moglia; F. Novelli; M. Piccinini; M. Mostert; MT Rinaudo; A. Chiò; A. Calvo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/148854
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