Abstract |
Transactivation response (TAR) DNA-binding protein of Mr 43 kDa (TDP-43) is a major component of the tau-negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP-43 proteinopathy. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role for the pathological process. In cultured cells, transfected C-terminal fragments of TDP-43 are more prone to form aggregates than full-length TDP-43. Transfecting the C-terminal fragment of TDP-43 harboring pathogenic mutations of TDP-43 gene identified in familial and sporadic ALS cases into cells enhanced the aggregate formation. Furthermore, we found that methylene blue and dimebon inhibit aggregation of TDP-43 in these cellular models. Understanding the mechanism of phosphorylation and truncation of TDP-43 and aggregate formation may be crucial for clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapeutics.
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Authors | Tetsuaki Arai, Masato Hasegawa, Takashi Nonoka, Fuyuki Kametani, Makiko Yamashita, Masato Hosokawa, Kazuhiro Niizato, Kuniaki Tsuchiya, Zen Kobayashi, Kenji Ikeda, Mari Yoshida, Mitsumoto Onaya, Hiroshige Fujishiro, Haruhiko Akiyama |
Journal | Neuropathology : official journal of the Japanese Society of Neuropathology
(Neuropathology)
Vol. 30
Issue 2
Pg. 170-81
(Apr 2010)
ISSN: 1440-1789 [Electronic] Australia |
PMID | 20102522
(Publication Type: Journal Article, Review)
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Chemical References |
- DNA-Binding Proteins
- alpha-Synuclein
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Topics |
- Amyotrophic Lateral Sclerosis
(metabolism, pathology)
- Brain
(metabolism, pathology)
- DNA-Binding Proteins
(metabolism)
- Frontotemporal Lobar Degeneration
(metabolism, pathology)
- Humans
- Inclusion Bodies
(metabolism, pathology)
- Phosphorylation
- alpha-Synuclein
(metabolism)
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