title: Phosphorylated TDP-43 becomes resistant to cleavage by calpain: A regulatory role for phosphorylation in TDP-43 pathology of ALS/FTLD.
abstract: TAR DNA-binding protein-43 (TDP-43) pathology, which includes the presence of abnormal TDP-43-containing inclusions with a loss of nuclear TDP-43 in affected neurons, is a pathological hallmark of amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobar degeneration (FTLD). TDP-43 in the pathological brains and spinal cords of ALS/FTLD patients is abnormally fragmented and phosphorylated. It is believed that the generation of aggregation-prone TDP-43 fragments initiates TDP-43 pathology, and we previously reported that calpain has an important role in the generation of such aggregation-prone TDP-43 fragments. However, the role of phosphorylation in TDP-43 pathology has not been largely elucidated, despite previous observations that several kinases and their kinases are involved in TDP-43 phosphorylation. Here, we investigated the role of TDP-43 phosphorylation in the calpain-dependent cleavage of TDP-43 and found that phosphorylated, full-length TDP-43 and calpain-dependent TDP-43 fragments were more resistant to cleavage by calpain than endogenous full-length TDP-43 was. These results suggest that both phosphorylated and calpain-cleaved TDP-43 fragments persist intracellularly for a length of time that is sufficient for self-aggregation, thereby serving as seeds for inclusions.
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takenari
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Teramoto
authors.affiliation: Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Clinical Research Center for Medicine, International University of Health and Welfare, 6-1-14 Konodai, Ichikawa, Chiba 272-0827, Japan. Electronic address: kwak-tky@umin.ac.jp.
authors.forename: Shin
authors.initials: S
authors.lastname: Kwak
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D057174:Frontotemporal Lobar Degeneration / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D066329:Protein Aggregates
chemical_list: D004268:DNA-Binding Proteins; D066329:Protein Aggregates; C000598624:TARDBP protein, human; D002154:Calpain
keywords: AMPA receptor; Adenosine deaminase acting on RNA 2 (ADAR2); Amyotrophic lateral sclerosis (ALS); Calpain; GluA2; RNA editing; TDP-43