title: [Calpain plays a crucial role in TDP-43 pathology].
abstract: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease affecting healthy middle-aged individuals. Mislocalization of TAR DNA binding protein of 43 kDa (TDP-43) or TDP-43 pathology observed in the spinal motor neurons is the pathological hallmark of ALS. The mechanism generating TDP-43 pathology remained uncertain. Several reports suggested that cleavage of TDP-43 into aggregation-prone fragments might be the earliest event. Therefore, elucidation of the protease(s) that is responsible for TDP-43 cleavage in the motor neurons is awaited. ALS-specific molecular abnormalities other than TDP-43 pathology in the motor neurons of sporadic ALS patients include inefficient RNA editing at the GluA2 glutamine/arginine (Q/R) site, which is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2). We have developed the conditional ADAR2 knockout (AR2) mice, in which the ADAR2 gene is targeted in motor neurons. We found that Ca(2+)-dependent cysteine protease calpain cleaved TDP-43 into aggregation-prone fragments, which initiated TDP-43 mislocalization in the motor neurons expressing abnormally abundant Ca(2+)-permeable AMPA receptors. Here we summarized the molecular cascade leading to TDP-43 pathology observed in the motor neurons of AR2 mice and discussed possible roles of dysregulation of calpain-dependent cleavage of TDP-43 in TDP-43 pathology observed in neurological diseases in general.
authors: Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo.
authors: Takenari
authors: T
authors: Yamashita
authors: Shin
authors: S
authors: Kwak
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology; D002154:Calpain / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism; D017393:RNA Editing; D018091:Receptors, AMPA / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology
chemical_list: D004268:DNA-Binding Proteins; D018091:Receptors, AMPA; C000598624:TARDBP protein, human; D002154:Calpain