title: TDP-43 pathology in sporadic ALS occurs in motor neurons lacking the RNA editing enzyme ADAR2.
abstract: Both the appearance of cytoplasmic inclusions containing phosphorylated TAR DNA-binding protein (TDP-43) and inefficient RNA editing at the GluR2 Q/R site are molecular abnormalities observed specifically in motor neurons of patients with sporadic amyotrophic lateral sclerosis (ALS). The purpose of this study is to determine whether a link exists between these two specific molecular changes in ALS spinal motor neurons. We immunohistochemically examined the expression of adenosine deaminase acting on RNA 2 (ADAR2), the enzyme that specifically catalyzes GluR2 Q/R site-editing, and the expression of phosphorylated and non-phosphorylated TDP-43 in the spinal motor neurons of patients with sporadic ALS. We found that all motor neurons were ADAR2-positive in the control cases, whereas more than half of them were ADAR2-negative in the ALS cases. All ADAR2-negative neurons had cytoplasmic inclusions that were immunoreactive to phosphorylated TDP-43, but lacked non-phosphorylated TDP-43 in the nucleus. Our results suggest a molecular link between reduced ADAR2 activity and TDP-43 pathology.
authors.affiliation: Department of Internal Medicine, Asahikawa Medical College, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Aizawa
authors.forename: Jun
authors.initials: J
authors.lastname: Sawada
authors.forename: Takuto
authors.initials: T
authors.lastname: Hideyama
authors.forename: Takenari
authors.initials: T
authors.lastname: Yamashita
authors.forename: Takayuki
authors.initials: T
authors.lastname: Katayama
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hasebe
authors.forename: Takashi
authors.initials: T
authors.lastname: Kimura
authors.forename: Osamu
authors.initials: O
authors.lastname: Yahara
authors.forename: Shin
authors.initials: S
authors.lastname: Kwak
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency / Q000378:metabolism*; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D016601:RNA-Binding Proteins; D051381:Rats; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D004268:DNA-Binding Proteins; D016601:RNA-Binding Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase