Mechanism for TDP-43 pathology in ALS Calcium-permeable AMPA receptor-mediated calpain activation cleaves TDP-43 into aggregation-prone fragments
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)
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Labo teamkwak (Japanese)