Calpain plays a crucial role in TDP-43 pathology

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease affecting healthy middleaged 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.