ATXN3 and Machado-Joseph disease: Moreover, triggering calpain activation in MJD mice by genetically depleting CAST led to a worsening of the disease-associated molecular and behavioral characteristics, whereas CAST overexpression in a further study ameliorated pathological hallmarks including polyQ-expanded Atx3 cleavage, mislocalization, and aggregation, and neuronal loss (Simões et al., 2012; Hübener et al., 2013).