Selective loss of dopaminergic neurons in the Substantia nigra following tyrosine hydroxylase immuno-reactivity | © dkfz.de

Our group is interested in the analysis of neurodegenerative processes by focusing on the role of the nucleolus in neuronal survival. The nucleolus, the site of rRNA synthesis, represents an important stress sensor and mediates stress response involving the transcription factor p53. To analyze the impact of nucleolar activity on neuronal survival, we have generated with the Cre-loxP system mutant mice in which the transcription factor TIF-IA, essential for the regulation of rRNA synthesis, is targeted in specific neurons. We observed that loss of TIF-IA in neuronal progenitors results in loss of neurons eventually leading to mice born without a brain. Disruption of nucleolar activity following TIF-IA gene ablation results in stabilization of p53. Inactivation of TIF-IA in mature neurons e.g. dopaminergic neurons leads to mice with a phenotype closely resembling Parkinson´s disease (PD). This model is characterized by progressive loss of dopaminergic neurons, depletion of dopamine in the striatum and marked deficiency in motor performance. The finding that in patients the nucleolus is disrupted, suggests that nucleolar perturbation is involved in the neurodegenerative process. We are currently investigating the possible role of the nucleolus for the pathogenesis of PD and other neurodegenerative diseases.