title: [TDP-43 proteinopathies, toward understanding of the molecular pathogenesis].
abstract: The TDP-43 proteinopathies: Toward understanding of the molecular pathogenesis. TAR DNA binding protein of 43 kDa (TDP-43), a heterogeneous nuclear ribonucleoprotein was identified as a major component of ubiquitin-positive inclusions in FTLD and ALS, and the concept of TDP-43 proteinopathies was proposed. Immunoblot and immunohistochemical analyses using multiple anti-phosphorylated TDP-43 antibodies revealed that hyperphosphorylated 18-26 kDa C-terminal fragments in addition to the full-length TDP-43 are major constituents of inclusions in FTLD-U and ALS. Recent discovery of mutations in the TDP-43 gene in familial and sporadic ALS, indicating that abnormality of TDP-43 protein cause neurodegeneration. It also strongly suggests that aggregation of TDP-43 or the process is responsible for neurodegeneration in FTLD-U and ALS. To investigate the molecular mechanisms of aggregation of TDP-43, we have established two cellular models for intracellular aggregates of TDP-43 similar to those in brains of TDP-43 proteinopathies patients. The first consists of SH-SY5Y cells expressing mutant TDP-43 that lacks both the nuclear localization signal (NLS) and residues 187-192 (deltaNLS & 187-192). The second model consists of SH-SY5Y cells expressing an aggregation-prone TDP-43 C-terminal fragment as a green fluorescent protein (GFP)-fusion. In these cells, round structures positive for both anti-pS409/410 and anti-Ub are observed. These results suggest that intracellular localization of TDP-43, truncation of TDP-43 and proteasomal dysfunction of cells may be involved in the pathological process of TDP-43 proteinopathies. We also found that two small compounds that have been reported to be beneficial in phase II clinical trials of Alzheimer's disease, inhibited the formation of TDP-43 aggregates in these two cellular models, suggesting that these compounds may be effective for the treatment of ALS and FTLD-U.
authors.affiliation: Department of Molecular Neurobiology, Tokyo Institute of Psychiatry.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamashita
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Kametani
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hashizume
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D017322:Clinical Trials, Phase II as Topic; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015195:Drug Design; D006801:Humans; D009154:Mutation; D019913:Nuclear Localization Signals; D010766:Phosphorylation; D057177:TDP-43 Proteinopathies / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D025801:Ubiquitin
chemical_list: D004268:DNA-Binding Proteins; D019913:Nuclear Localization Signals; D025801:Ubiquitin