Damaging calpain overactivation has been associated with the pathogenic reduction of the natural endogenous calpain inhibitor calpastatin in vivo models of Alzheimer’s disease (Rao et al., 2014), amyotrophic lateral sclerosis (Rao et al., 2016) and Huntington’s disease (Hu et al., 2021). Here, CAST is linked to Huntington disease.