PhD defence A.M. (Mattijs) Punt

Below is a brief summary of the dissertation:

Angelman syndrome (AS) is a neurodevelopmental disorder caused by deletions or mutations in the maternal copy of the UBE3A gene. These genetic defects lead to a neuronal deficiency of the UBE3A protein or impair its function. Under normal circumstances, UBE3A ubiquitinates specific proteins (targets), thereby facilitating their degradation by the 26S proteasome. Following neuronal loss of functional UBE3A, these targets accumulate, which is believed to be the basis for the pathophysiology of AS (see also the General Introduction). The aim of this thesis was to improve our understanding of the UBE3A protein and its mechanisms in disease. This was done by mechanistically investigating the subcellular localization of UBE3A, characterizing the effect of patient-associated UBE3A mutations, performing studies to determine whether certain nuclear processes are affected by the loss of UBE3A, and evaluating to what extent overexpression of UBE3A leads to disease-related phenotypes in mice.