期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 21, 页码 18664-18672出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.231209
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [22240037, 22110004, 22770162, 21390274]
- Core Research for Evolutional Science and Technology of Japan Science and Technology Agency
- Japanese Health and Labor Sciences Research Grant
- Strategic Research Program for Brain Science
- Naito Foundation
- Grants-in-Aid for Scientific Research [22110004, 22240037, 22770162, 21390274] Funding Source: KAKEN
The transactivation response element (TAR) DNA-binding protein-43 (TDP-43) is a nuclear protein that normally regulates transcription and splicing. Abnormal accumulation of insoluble inclusions containing TDP-43 has been recently reported in the affected tissues of amyotrophic lateral sclerosis (ALS) patients. Here, we show that intracellular aggregation of TDP-43 can be triggered by transduction of fibrillar aggregates prepared from in vitro functional TDP-43. Sarkosyl is found to be incapable of solubilizing those intracellularly seeded aggregates of TDP-43, which is consistent with the observation that TDP-43 inclusions in ALS patients are sarkosyl-insoluble. In addition, intracellular seeding in our cell models reproduces ubiquitination of TDP-43 aggregates, which is another prominent feature of TDP-43 inclusions in ALS patients. Although it has been so far difficult to initiate disease-associated changes of TDP-43 using cultured cell models, we propose that a seeding reaction is a key to construct a model to monitor TDP-43 pathologies.
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