Mechanism for TDP-43 pathology in ALS
Calcium-permeable AMPA receptor-mediated calpain activation cleaves TDP-43 into aggregation-prone fragments
Graduate School of Medicine / Faculty of Medicine
Guest Researcher Shin Kwak and Project Researcher Takenari Yamashita at the University of Tokyo’s Graduate School of Medicine, Center for Disease Biology and Integrative Medicine, in collaboration with a RIKEN group, have discovered the molecular mechanism whereby TDP-43 pathology, a pathological hallmark of amyotrophic lateral sclerosis (ALS), occurs in ALS motor neurons. TDP-43 pathology includes absence of TDP-43 from the nucleus and the formation of abnormal cytoplasmic inclusions, and is believed to be involved in the pathogenesis of ALS, but how TPD-43 pathology is formed was poorly understood. This paper demonstrates that the abnormally calcium-permeable AMPA receptor (an ionotropic subtype of the glutamate receptor)-mediated activation of calpain, a calcium-dependent cysteine protease, cleaves TDP-43 into aggregation-prone fragments, which initiates TDP-43 pathology. This finding provides an answer to the unresolved molecular link between the two ALS-specific molecular abnormalities, TDP-43 and down-regulation of ADAR2, an enzyme catalyzing RNA editing (post-transcriptional modification of nucleotides), both of which co-occur in the same ALS motor neurons. Down-regulation of ADAR2 results in the up-regulation of the abnormally calcium-permeable AMPA receptor by failure of naturally occurring RNA editing of GluA2, a subunit of the AMPA receptor. Furthermore, expression of unedited GluA2 is a cause of death of motor neurons in conditional ADAR2 knockout mice (AR2), a mechanistic model of sporadic ALS. The researchers found that activated calpain specifically mediates TDP-43 pathology in AR2 mice. Additional demonstration of calpain-dependent TDP-43 fragments in the spinal cord and brain of ALS patients, and high vulnerability of ALS-linked mutant TDP-43 to cleavage by calpain support the crucial role of the calpain-dependent cleavage of TDP-43 in the ALS pathology.
Press release [PDF] (Japanese)
Masahiro Yuki, Hiromasa Tanaka, Kouitsu Sasaki, Yoshihiro Miyake, Kazunari Yoshizawa, Yoshiaki Nishibayashi,
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Labo teamkwak (Japanese)