Reduced cellular Ca(2+) availability enhances TDP-43 cleavage by apoptotic caspases.
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.
'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Department of Oncology, University of Turin, Turin, Italy.
Giovanni
G
De Marco
'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; Department of Oncology, University of Turin, Turin, Italy.
Annarosa
A
Lomartire
Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Turin, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Giorgia
G
Mandili
Department of Oncology, University of Turin, Turin, Italy.
Elisa
E
Lupino
Department of Oncology, University of Turin, Turin, Italy.
Barbara
B
Buccinnà
Department of Oncology, University of Turin, Turin, Italy.
Cristina
C
Ramondetti
'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; CRESLA Turin, AOU Città della Salute e della Scienza, Turin, Italy.
Cristina
C
Moglia
Center for Experimental Research and Medical Studies (CeRMS), University of Turin, Turin, Italy; Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
Francesco
F
Novelli
Department of Oncology, University of Turin, Turin, Italy.
Marco
M
Piccinini
Department of Public Health and Pediatric Sciences, University of Turin, Turin, Italy.
Michael
M
Mostert
Department of Oncology, University of Turin, Turin, Italy. Electronic address: mariateresa.rinaudo@unito.it.
Maria Teresa
MT
Rinaudo
'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; CRESLA Turin, AOU Città della Salute e della Scienza, Turin, Italy.
Adriano
A
Chiò
'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy; CRESLA Turin, AOU Città della Salute e della Scienza, Turin, Italy.
Andrea
A
Calvo
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002118:Calcium / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D051379:Mice
D004268:DNA-Binding Proteins; D020169:Caspases; D002118:Calcium
Apoptosis; Ca(2+) deprivation; Caspase; TDP-43 cleavage