Biochemical and histopathological alterations in TAR DNA-binding protein-43 after acute ischemic stroke in rats.

Abstract

Nuclear factor TAR DNA-binding protein-43 (TDP-43) is considered to play roles in pathogenesis of human neurodegenerative diseases, so-called TDP-43 proteinopathy, via its proteolytic cleavage, abnormal phosphorylation, subcellular redistribution, and insolubilization generating TDP-43-positive neuronal intracellular inclusions. The purpose of this study was to elucidate biochemical and histopathological alternations in TDP-43 specific to acute ischemic stroke. Adult male rats were subjected to a 90-min middle cerebral artery occlusion. We examined the proteolytic cleavage, phosphorylation, subcellular localization, and solubility of TDP-43 by immunoblottings and histopathological examinations using the ischemic and sham-operated cortex. The level of full-length TDP-43 (43 kDa) decreased and that of the 25-kDa C-terminal fragment increased after acute ischemic stroke, which can be explained by proteolytic cleavage of TDP-43. Cytoplasmic redistribution and altered nuclear distribution of TDP-43 was observed after acute ischemic stroke, whereas abnormal phosphorylation and insolubilization of TDP-43 as well as formation of intracellular inclusions were not observed. Ischemic neurons with the cytoplasmic redistribution of TDP-43 expressed ubiquitin and activated caspase 3 and were terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling-positive. In conclusion, biochemical and histopathological alterations in TDP-43 were identified in rats after acute ischemic stroke, although there was very less similarity between TDP-43 alterations observed in acute ischemic stroke and those observed in TDP-43 proteinopathy.

• Authors: Masato Kanazawa, Akiyoshi Kakita, Hironaka Igarashi, Tetsuya Takahashi, Kunio Kawamura, Hitoshi Takahashi, Tsutomu Nakada, Masatoyo Nishizawa, Takayoshi Shimohata
• Journal: Journal of neurochemistry (J Neurochem) Vol. 116 Issue 6 Pg. 957-65 (Mar 2011) ISSN: 1471-4159 [Electronic] England
• PMID: 20557425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry.

Chemical References

• DNA-Binding Proteins
• Enzyme Inhibitors
• Oligopeptides
• Ubiquitin
• benzyloxycarbonyl-aspartyl(OMe)-isoleucyl-prolyl-aspartyl(OMe) fluoromethylketone

Topics

• Animals
• Brain (pathology)
• Cell Count (methods)
• DNA-Binding Proteins (metabolism)
• Disease Models, Animal
• Enzyme Inhibitors (administration & dosage)
• Gene Expression Regulation (drug effects, physiology)
• In Situ Nick-End Labeling
• Injections, Intraventricular (methods)
• Ischemia (complications)
• Male
• Molecular Weight
• Neurons (metabolism, pathology)
• Oligopeptides (administration & dosage)
• Phosphorylation (drug effects, physiology)
• Protein Transport (drug effects)
• Rats
• Rats, Sprague-Dawley
• Statistics, Nonparametric
• Stroke (etiology, metabolism, pathology)
• Time Factors
• Ubiquitin (metabolism)