title: A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology.
abstract: Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 co-localize in the motor neurons of amyotrophic lateral sclerosis patients, but how they are linked is not clear. Here we demonstrate that activation of calpain, a Ca2+-dependent cysteine protease, by upregulation of Ca2+-permeable AMPA receptors generates carboxy-terminal-cleaved TDP-43 fragments and causes mislocalization of TDP-43 in the motor neurons expressing glutamine/arginine site-unedited GluA2 of conditional ADAR2 knockout (AR2) mice that mimic the amyotrophic lateral sclerosis pathology. These abnormalities are inhibited in the AR2res mice that express Ca2+-impermeable AMPA receptors in the absence of ADAR2 and in the calpastatin transgenic mice, but are exaggerated in the calpastatin knockout mice. Additional demonstration of calpain-dependent TDP43 fragments in the spinal cord and brain of amyotrophic lateral sclerosis patients, and high vulnerability of amyotrophic lateral sclerosis-linked mutant TDP43 to cleavage by calpain support the crucial role of the calpain-dependent cleavage of TDP43 in the amyotrophic lateral sclerosis pathology.
authors.affiliation: CREST, Japan Science and Technology Agency, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Takenari
authors.initials: T
authors.lastname: Yamashita
authors.forename: Takuto
authors.initials: T
authors.lastname: Hideyama
authors.forename: Kosuke
authors.initials: K
authors.lastname: Hachiga
authors.forename: Sayaka
authors.initials: S
authors.lastname: Teramoto
authors.forename: Jiro
authors.initials: J
authors.lastname: Takano
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Shin
authors.initials: S
authors.lastname: Kwak
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D002154:Calpain / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D002154:Calpain