The role of gene silencing for maintenance of differentiated dopaminergic and serotonergic neuronal identity and function in healthy aging and disease

How stable silencing of alternative gene programs is maintained once a neuronal identity has been established remain largely unexplored.

A central question is if repression of genes is continuously regulated or a consequence of earlier fate decisions which have permanently modified the chromatin architecture.

Failure to maintain identity threatens neuronal function and can potentially lead to psychiatric or neurodegenerative disease.

We will investigate the functional importance of polycomb mediated gene silencing for maintenance of murine and human dopaminergic and serotonergic neuronal identity.

The project addresses the importance of polycomb repressive complex 2 (PRC2)-mediated repression for maintaining chromatin structure, gene expression, neuronal identity, neuronal population integrity and behavior.

The proposal integrates basal mechanistic research in transgenic mouse models with a focus on the role of PRC2-mediated gene repression in human mDA-neurons during normal aging and in PD-patients as well as the functional role for PRC2 in human embryonic stem cell derived dopamine neurons in a mouse model of Parkinson´s disease.

In addition, unraveling these mechanisms may provide insights leading to novel ways to tackle mental and neurodegenerative disease.