Calpain-dependent disruption of nucleo-cytoplasmic transport in ALS motor neurons

• Published in: Scientific reports 2017-01, Vol.7 (1), p.39994-39994, Article 39994
• Main Authors: Yamashita, Takenari, Aizawa, Hitoshi, Teramoto, Sayaka, Akamatsu, Megumi, Kwak, Shin
• Format: Article
• Language: English
• Subjects: 13/109; 14; 14/1; 38/22; 38/23; 38/77; 631/378/340; 64/60; 692/617/375/1917/1285; 82/80; Active Transport, Cell Nucleus - physiology; Adenosine; Adenosine deaminase; Adenosine Deaminase - deficiency; Adenosine Deaminase - genetics; alpha Karyopherins - metabolism; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - pathology; Animals; Axonal transport; Calcium - metabolism; Calcium permeability; Calcium signalling; Calpain; Calpain - metabolism; Cell death; Disease Models, Animal; DNA-Binding Proteins - metabolism; DNA-directed RNA polymerase; Elongation; Humanities and Social Sciences; Humans; Immunoreactivity; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor neurons; Motor Neurons - metabolism; Motor Neurons - pathology; Motor task performance; multidisciplinary; Nuclear Pore - metabolism; Nuclear Pore Complex Proteins - metabolism; Nucleoporins; Pathogenesis; Phosphorylation; Receptors, AMPA - metabolism; RNA Polymerase II - metabolism; RNA-Binding Proteins - genetics; Rodents; Science; Science (multidisciplinary); Spinal Cord - metabolism; Spinal Cord - pathology; Transcription; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep39994

Nuclear dysfunction in motor neurons has been hypothesized to be a principal cause of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we investigated the mechanism by which the nuclear pore complex (NPC) is disrupted in dying motor neurons in a mechanistic ALS mouse model (adenosine deaminase acting on RNA 2 (ADAR2) conditional knockout (AR2) mice) and in ALS patients. We showed that nucleoporins (Nups) that constituted the NPC were cleaved by activated calpain via a Ca 2+ -permeable AMPA receptor-mediated mechanism in dying motor neurons lacking ADAR2 expression in AR2 mice. In these neurons, nucleo-cytoplasmic transport was disrupted, and the level of the transcript elongation enzyme RNA polymerase II phosphorylated at Ser2 was significantly decreased. Analogous changes were observed in motor neurons lacking ADAR2 immunoreactivity in sporadic ALS patients. Therefore, calpain-dependent NPC disruption may participate in ALS pathogenesis, and inhibiting Ca 2+ -mediated cell death signals may be a therapeutic strategy for ALS.