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Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy.

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.
AuthorsTetsuaki 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
JournalNeuropathology : official journal of the Japanese Society of Neuropathology (Neuropathology) Vol. 30 Issue 2 Pg. 170-81 (Apr 2010) ISSN: 1440-1789 [Electronic] Australia
PMID20102522 (Publication Type: Journal Article, Review)
Chemical References
  • DNA-Binding Proteins
  • alpha-Synuclein
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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