| TDP-43-induced death is associated with altered regulation of BIM and Bcl-xL and attenuated by caspase-mediated TDP-43 cleavage. | |
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MedLine Citation:
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PMID: 21339291 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Abnormal aggregates of transactive response DNA-binding protein-43 (TDP-43) and its hyperphosphorylated and N-terminal truncated C-terminal fragments (CTFs) are deposited as major components of ubiquitinated inclusions in most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). The mechanism underlying the contribution of TDP-43 to the pathogenesis of these neurodegenerative diseases remains unknown. In this study, we found that a 2-5-fold increase in TDP-43 expression over the endogenous level induced death of NSC34 motor neuronal cells and primary cortical neurons. TDP-43-induced death is associated with up-regulation of Bim expression and down-regulation of Bcl-xL expression. siRNA-mediated reduction of Bim expression attenuates TDP-43-induced death. Accumulated evidence indicates that caspases are activated in neurons of ALS and FTLD-U patients, and activated caspase-mediated cleavage of TDP-43 generates CTFs of TDP-43. Here, we further found that the ER (endoplasmic reticulum) stress- or staurosporine-mediated activation of caspases leads to cleavage of TDP-43 at Asp(89) and Asp(169), generating CTF35 (TDP-43-(90-414)) and CTF27 (TDP-43-(170-414)) in cultured neuronal cells. In contrast to TDP-43, CTF27 is unable to induce death while it forms aggregates. CTF35 was weaker than full-length TDP-43 in inducing death. A cleavage-resistant mutant of TDP-43 (TDP-43-D89E/D169E) showed stronger death-inducing activity than wild-type TDP-43. These results suggest that disease-related activation of caspases may attenuate TDP-43-induced toxicity by promoting TDP-43 cleavage. |
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Authors:
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Hiroaki Suzuki; Kikyo Lee; Masaaki Matsuoka |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-02-21 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-04-11 Completed Date: 2011-06-28 Revised Date: 2012-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 13171-83 Citation Subset: IM |
Affiliation:
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Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amyotrophic Lateral Sclerosis
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genetics,
metabolism* Animals Apoptosis Regulatory Proteins / genetics, metabolism* Caspases / genetics, metabolism* Cell Death / drug effects, genetics Cell Line DNA-Binding Proteins Endoplasmic Reticulum / genetics, metabolism Enzyme Inhibitors / pharmacology Frontotemporal Lobar Degeneration / genetics, metabolism* Gene Expression Regulation / drug effects, genetics Humans Inclusion Bodies / genetics, metabolism Membrane Proteins / genetics, metabolism* Mice Mice, Inbred ICR Neurons / metabolism Proto-Oncogene Proteins / genetics, metabolism* Staurosporine / pharmacology Ubiquitin / genetics, metabolism Unfolded Protein Response / drug effects, genetics bcl-X Protein / genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Apoptosis Regulatory Proteins; 0/BCL2L1 protein, human; 0/Bcl-2-like protein 11; 0/Bcl2l1 protein, mouse; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/Membrane Proteins; 0/Proto-Oncogene Proteins; 0/Ubiquitin; 0/bcl-X Protein; 0/protein TDP-43; 62996-74-1/Staurosporine; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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