title: A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions.
abstract: The transactivation response element (TAR) DNA-binding protein-43 (TDP-43) is a nuclear protein that normally regulates transcription and splicing. Abnormal accumulation of insoluble inclusions containing TDP-43 has been recently reported in the affected tissues of amyotrophic lateral sclerosis (ALS) patients. Here, we show that intracellular aggregation of TDP-43 can be triggered by transduction of fibrillar aggregates prepared from in vitro functional TDP-43. Sarkosyl is found to be incapable of solubilizing those intracellularly seeded aggregates of TDP-43, which is consistent with the observation that TDP-43 inclusions in ALS patients are sarkosyl-insoluble. In addition, intracellular seeding in our cell models reproduces ubiquitination of TDP-43 aggregates, which is another prominent feature of TDP-43 inclusions in ALS patients. Although it has been so far difficult to initiate disease-associated changes of TDP-43 using cultured cell models, we propose that a seeding reaction is a key to construct a model to monitor TDP-43 pathologies.
authors: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan.
authors: Yoshiaki
authors: Y
authors: Furukawa
authors: Kumi
authors: K
authors: Kaneko
authors: Shoji
authors: S
authors: Watanabe
authors: Koji
authors: K
authors: Yamanaka
authors: Nobuyuki
authors: N
authors: Nukina
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D020218:Response Elements; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000097:blood; D012995:Solubility
chemical_list: D004268:DNA-Binding Proteins; C025231:sarkosyl; D012521:Sarcosine