A central focus of research is on disease mechanisms of progressive myoclonus epilepsy EPM1 utilizing cystatin B –deficient (Cstb-/-) mice as a model. We previously showed that cystatin B has a role in regulating neuronal survival during oxidative stress, which is at least partly mediated by cathepsin B signaling. More recently, we demonstrated that early microglial activation and neuroinflammation centrally contribute to neuronal dysfunction and death in Cstb-/- mice. We are currently investigating the molecular mechanisms associated with microglial activation and dysfunction, a long-term aim being the identification of novel target molecules and the development of anti-inflammatory therapies to alleviate disease progression in Cstb-/- mice.
Gene identification is focused on progressive myoclonus epilepsy (PME) syndromes and severe early childhood-onset progressive encephalopathies using exome sequencing. The group recently reported identification of a recurrent de novo mutation in KCNC1 causing a dominant-negative loss-of-function effect on the KV3 voltage-gated potassium channel as a major underlying cause of PME worldwide. The group is also involved in analysis of the molecular genetics basis of generalized genetic epilepsies, which are multifactorial in origin. Gene identification involves collaboration with large international consortia.