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

Yamashita, Takenari  ,  Aizawa, Hitoshi  ,  Teramoto, Sayaka  ,  Akamatsu, Megumi  ,  Kwak, Shin

7p.39994 , 2017-01-03 , Nature Publishing Group
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 Ca2+-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 Ca2+-mediated cell death signals may be a therapeutic strategy for ALS.
UTokyo Research掲載「核と細胞質間の分子輸送経路の破綻が筋萎縮性側索硬化症に関与」 URI:
UTokyo Research "Disruption of molecule transport pathway between nucleus and cytoplasm involved in ALS" URI:

Number of accesses :  

Other information