In neurons, moderate calpain-1 activation (as we observe in IBM samples) causes cleavage of TDP-43 into aggregation-prone fragments, promoting the TDP-43 cytoplasmic mislocalization (TDP-43 proteinopathy) observed in amyotrophic lateral sclerosis [1, 57]. This evidence concerns the gene CAPN1 and amyotrophic lateral sclerosis.