Rett syndrome, MECP2 and therapeutic strategies
The development of the iPS cell technology has revolutionized our ability to study development and diseases in defined in vitro cell culture systems. The talk will focus on Rett Syndrome and discuss two topics: (i) the use of gene editing as an approach to therapy and (ii) the role of MECP2 in gene expression (i) The mutation of the X-linked MECP2 gene is causative for the disease. In a female patient, every cell has a wt copy that is, however, in 50% of the cells located on the inactive X chromosome. We have used epigenetic gene editing tools to activate the wt MECP2 allele on the inactive X chromosome. (ii) MECP2 is thought to act as repressor of gene expression. I will present data which show that MECP2 binds to Pol II and acts as an activator for thousands of genes. The target genes are significantly enriched for Autism related genes. Our data challenge the established model of MECP2’s role in gene expression and suggest novel therapeutic approaches.
The cellular basis of Parkinson’s disease
Parkinson’s disease is affects millions of people around the world. The disease is characterized by typical movement defects that are caused by the loss of dopaminergic neurons, but several very debilitating non-motor symptoms occur more than 10 years before the motor symptoms. I will discuss how we study these non-motor symptoms including sleep disturbances and olfactory defects using large collections of knock in fruit flies that model the numerous familial forms of Parkinson’s disease as well as using human iPS cells from patients. A common emerging theme are defects in protein homeostasis that in specific neuronal cell types, cause cellular defects that explain the Parkinson-relevant phenotypes. Our work reveals the mechanisms that cause early defects in Parkinson’s disease and it opens therapeutic avenues to start tackling this disease.