title: Prion-like properties of pathological TDP-43 aggregates from diseased brains.
abstract: TDP-43 is the major component protein of ubiquitin-positive inclusions in brains of patients with frontotemporal lobar degeneration (FTLD-TDP) or amyotrophic lateral sclerosis (ALS). Here, we report the characterization of prion-like properties of aggregated TDP-43 prepared from diseased brains. When insoluble TDP-43 from ALS or FTLD-TDP brains was introduced as seeds into SH-SY5Y cells expressing TDP-43, phosphorylated and ubiquitinated TDP-43 was aggregated in a self-templating manner. Immunoblot analyses revealed that the C-terminal fragments of insoluble TDP-43 characteristic of each disease type acted as seeds, inducing seed-dependent aggregation of TDP-43 in these cells. The seeding ability of insoluble TDP-43 was unaffected by proteinase treatment but was abrogated by formic acid. One subtype of TDP-43 aggregate was resistant to boiling treatment. The insoluble fraction from cells harboring TDP-43 aggregates could also trigger intracellular TDP-43 aggregation. These results indicate that insoluble TDP-43 has prion-like properties that may play a role in the progression of TDP-43 proteinopathy.
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan. nonaka-tk@igakuken.or.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Masami
authors.initials: M
authors.lastname: Masuda-Suzukake
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Arai
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Akatsu
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Obi
authors.forename: Mari
authors.initials: M
authors.lastname: Yoshida
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.forename: David M A
authors.initials: DM
authors.lastname: Mann
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D017209:Apoptosis; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D055354:Exosomes / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D010766:Phosphorylation; D058105:Polymerization; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011489:Protein Denaturation; D059748:Proteolysis; D054875:Ubiquitination
chemical_list: D046988:Proteasome Endopeptidase Complex