Rinsho Shinkeigaku (Clinical Neurology)

Symposium 33

Calpain plays a crucial role in TDP-43 pathology

Takenari Yamashita, Ph.D.1) and Shin Kwak, M.D. Ph.D.2)

1)Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo
2)International University of Health and Welfare

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 Ca2+-dependent cysteine protease calpain cleaved TDP-43 into aggregation-prone fragments, which initiated TDP-43 mislocalization in the motor neurons expressing abnormally abundant Ca2+-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.
Full Text of this Article in Japanese PDF (815K)

(CLINICA NEUROL, 54: 1151|1154, 2014)
key words: amyotrophic lateral sclerosis, TDP-43 pathology, Calpain, AMPA Receptor, Calcium signaling

(Received: 24-May-14)