Roles of excitotoxicity in pathogenesis of degenerative neurological diseases

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Presence of intracellular inclusion body is a pathological hallmark of degenerative neurological diseases but how these inclusions are formed is largely unknown. TDP-43 is a composite protein of inclusions seen in motor neurons of amyotrophic lateral sclerosis (ALS) and cortical neurons of frontotemporal lobar degeneration (FTLD) patients. We found that calcium-dependent cysteine protease calpain specifically cleaved C-terminal regions of TDP-43, thereby generating aggregation-prone fragments. We did not find α-synuclein-, Aβ-, or tau-containing inclusions in the mutant mice with abnormal calcium signaling.