Loss-of-function mutations in cystatin B (CSTB) cause progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1). Cstb-deficiency in mice leads to early alterations in GABAergic signaling, and causes neuroinflammation followed by progressive neurodegeneration, manifesting as progressive myoclonus and ataxia. The proteome of cerebellar synaptosomes of presymptomatic Cstb-/- mice were characterized by LC-ESI-MS/MS to gain insight into disease formation and progression.