Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy.
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.
Arai
Tetsuaki
T
Department of Psychogeriatrics, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, Tokyo, Japan.
Hasegawa
Masato
M
Nonoka
Takashi
T
Kametani
Fuyuki
F
Yamashita
Makiko
M
Hosokawa
Masato
M
Niizato
Kazuhiro
K
Tsuchiya
Kuniaki
K
Kobayashi
Zen
Z
Ikeda
Kenji
K
Yoshida
Mari
M
Onaya
Mitsumoto
M
Fujishiro
Hiroshige
H
Akiyama
Haruhiko
H
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051844:alpha-Synuclein / Q000378:metabolism
D004268:DNA-Binding Proteins; D051844:alpha-Synuclein