Modifying calpains and calpain-mediated cleavage with genetic means has been tested in different experimental set-ups in vitro and in vivo for HD and SCA3, such as by knocking out specific calpain isoforms (Menzies et al., 2015; Weber et al., 2020), overexpressing the endogenous inhibitor CAST (Simões et al., 2012; Menzies et al., 2015) or removing calpain cleavage sites (Gafni et al., 2004; Toonen et al., 2016; Weber et al., 2017; Simões et al., 2022). Here, CAST is linked to Huntington disease.