Reduced cellular Ca²⁺ availability enhances TDP-43 cleavage by apoptotic caspases

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• 作者：Giovanni De Marco^a ; ^b ; ¹ ; Annarosa Lomartire^a ; ^b ; ¹ ; Giorgia Mandili^c ; ^d ; Elisa Lupino^b ; Barbara Buccinnà ; ^b ; Cristina Ramondetti^b ; Cristina Moglia^a ; ^e ; Francesco Novelli^c ; ^d ; Marco Piccinini^b ; Michael Mostert^f ; Maria Teresa Rinaudo^b ; ^{mariateresa.rinaudo@unito.it" class="auth_mail} ; Adriano Chiò ; ^a ; ^e ; Andrea Calvo^a ; ^e
• 关键词：ALS ; amyotrophic lateral sclerosis ; BAPTA-AM ; 1 ; 2-bis (o-aminophenoxy) ethane-N ; N ; N&prime ; N&prime ; -tetraacetic acid acetoxymethyl ester ; BSA ; bovine serum albumin ; CHAPS ; 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate ; CoCl2 ; cobalt chloride ; DMEM ; Dulbecco's Modified Eagle Medium ; DTT ; dithiothreitol ; EDTA ; ethylenediaminetetraacetic acid ; ER ; endoplasmic reticulum ; FBS ; fetal bovine serum ; FTLD ; frontotemporal lobar degeneration ; HEPES ; 4-(2-hydroxyethyl)-1-piperazineethanesulfoni
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：April, 2014
• 年：2014
• 卷：1843
• 期：4
• 页码：725-734
• 全文大小：1398 K

文摘

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 Ca²⁺ 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 Ca²⁺, affects TDP-43 cleavage. Here we show that in various cell lineages with restricted Ca²⁺ 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 15 kDa, in addition to the well-known fragments of 35 and 25 kDa. 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.