title: Molecular analysis and biochemical classification of TDP-43 proteinopathy.
abstract: Amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TAR DNA-binding protein of 43 kDa pathology are progressive neurodegenerative diseases that are characterized by intracytoplasmic aggregates of hyperphosphorylated TAR DNA-binding protein of 43 kDa. These TAR DNA-binding protein 43 proteinopathies can be classified into subtypes, which are closely correlated with clinicopathological phenotypes, although the differences in the molecular species of TAR DNA-binding protein 43 in these diseases and the biological significance thereof, remain to be clarified. Here, we have shown that although the banding patterns of abnormally phosphorylated C-terminal fragments of TAR DNA-binding protein 43 differ between the neuropathological subtypes, these are indistinguishable between multiple brain regions and spinal cord in individual patients. Immunoblot analysis of protease-resistant TAR DNA-binding protein 43 demonstrated that the fragment patterns represent different conformations of TAR DNA-binding protein 43 molecular species in the diseases. These results suggest a new clinicopathological classification of TAR DNA-binding protein 43 proteinopathies based on their molecular properties.
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuji
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Kametani
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamashita
authors.forename: Masami
authors.initials: M
authors.lastname: Suzukake
authors.forename: Masato
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.forename: Masaki
authors.initials: M
authors.lastname: Takao
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saito
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: David M A
authors.initials: DM
authors.lastname: Mann
authors.forename: Akira
authors.initials: A
authors.lastname: Tamaoka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011487:Protein Conformation; D013116:Spinal Cord / Q000378:metabolism; D057177:TDP-43 Proteinopathies / Q000145:classification* / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins