This study clarifies a previously unknown mechanism that controls the activity of calpain proteases, enzymes that regulate protein processing and can contribute to neurological disease when dysregulated. The researchers found that KCTD7 partners with Cullin-3 to attach specific ubiquitin chains to calpains, not to target them for degradation, but to tune their activity. When this tagging mechanism is disrupted, such as in certain genetic deficiencies, calpains become hyperactive, driving excessive protein cleavage, activation of cell death pathways, and neurodegeneration. In mouse models, loss of KCTD7 led to brain degeneration and behavioral changes, and inhibiting calpain activity reduced these harmful effects, pointing to a potential therapeutic strategy for calpain-associated neurological disorders.