title: Chronic cerebral ischemia induces redistribution and abnormal phosphorylation of transactivation-responsive DNA-binding protein-43 in mice.
abstract: Transactivation-responsive DNA-binding protein 43 (TDP-43) is closely involved in the pathogenesis of frontotemporal lobar degeneration. The native form, but not phosphorylated form, of TDP-43 has been reported to redistribute during acute neuronal injuries. Here, we examined whether the expression of phosphorylated TDP-43 was altered following chronic neuronal injury. C57BL/6 mice were subjected to sham operation or bilateral common carotid artery stenosis (BCAS) using microcoils, and changes in proteolytic cleavage, phosphorylation, and subcellular redistribution of TDP-43 were examined by immunoblotting and immunohistochemistry. We also monitored the expression of importin β, which is involved in the transport of TDP-43. Immunoblotting showed an increase in phosphorylated TDP-43 in the nuclear fraction after BCAS using microcoils. Moreover, immunoreactivity toward phosphorylated TDP-43 was observed in the neuronal cytoplasm in the cerebral cortex and hippocampus, and importin β levels decreased after the operation. Immunoreactivity toward phosphorylated TDP-43 was partly colocalized with immunoreactivity toward caspase 3 in the neuronal cytoplasm. These results suggested that chronic cerebral ischemia induced redistribution and abnormal phosphorylation of TDP-43, which may be triggered by downregulation of importin β and may partly result in neuronal death.
authors: Department of Neurology, Graduate School of Medicine, Mie University, Japan. Electronic address: a-shindo@clin.medic.mie-u.ac.jp.
authors: Akihiro
authors: A
authors: Shindo
authors: Kenichiro
authors: K
authors: Yata
authors: Ryogen
authors: R
authors: Sasaki
authors: Hidekazu
authors: H
authors: Tomimoto
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D028961:beta Karyopherins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D028961:beta Karyopherins
keywords: ALS; Chronic cerebral ischemia; FTLD; Hippocampal sclerosis; NLS; PBS; Phosphorylation; TAR DNA-binding protein-43; TDP-43; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; nuclear localization signal; p-TDP-43; phosphate-buffered saline; phosphorylated transactivation-responsive DNA-binding protein-43; single-stranded DNA; ss-DNA; transactivation-responsive DNA-binding protein-43