Molecular mechanisms of neurodegeneration
Previous work of the laboratory focused on neurotrophic factor signaling in maintaining the functionality of the aging brain. We investigated the function of the Ret protein, the receptor for GDNF (glial cell line-derived neurotrophic factor) in the context of Parkinson disease. We had found a new molecular connection between Ret signaling for neuron survival, cellular stress and aging in a mouse model of Parkinson disease (Aron et al., 2010). More recently, we described a new mechanism of cell protection by Ret signaling in a Drosophila model of Parkinson disease (Klein et al., 2014).
Current work in the lab focusses on the role and pathological mechanism of toxic protein aggregates and the cellular defense systems that fight against these aggregates.
A common feature of many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis, is the deposition of amyloid-like proteins in nerve cells and sometimes in the surrounding extracellular matrix. A number of cellular defense mechanisms exist to clear damaged proteins from the cells. However, these defense strategies sometimes fail, leading to the accumulation of amyloid-like proteins and eventually to cell death. Although it is clear that aggregating proteins cause damage to the neurons, the molecular mechanisms of aggregate toxicity remain largely unknown.
We investigate the effects of aggregating proteins in primary neuronal cultures and in vivo in mouse models of neurodegenerative diseases. In cooperation with the departments of Ulrich Hartl, Matthias Mann and Wolfgang Baumeister (MPI of Biochemistry), we aim to use a multidisciplinary approach to characterize the formation of amyloid-like aggregates, their localization in the cell and their interactions with other proteins. To reveal common mechanisms relevant for different neurodegenerative diseases, we compare the aggregates formed by natural disease-causing proteins and by rationally designed artificial proteins.
To study the impact of aggregation on the cellular defense against toxic proteins, we are generating reporter mice in which the activity of those defense components can be visualized and measured. Crossing these reporter mice to disease models will enable us to monitor the status of the cellular defense systems at different stages of disease.