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Proteostasis in Neurodegenerative Disease

Thomas Jahn

Schaller Research Group at the University of Heidelberg and DKFZ

German Cancer Research Center

Im Neuenheimer Feld 581

69120 Heidelberg, Germany

The main interest of our lab is to advance our understanding of the molecular events triggered by protein misfolding and the subsequent impact of protein aggregation on cellular integrity.

One of the essential characteristics of living systems is the ability of their molecular components to self-assemble into functional structures and to balance their organisation within the cellular environment through the mechanism of homeostasis. It is clear that protein homeostasis, or proteostasis, is closely coupled to many other biological processes ranging from the trafficking of molecules to specific cellular locations to the regulation of the growth and differentiation of cells. In addition, only correctly folded proteins have the ability to remain soluble in crowded biological environments and to interact selectively with their natural partners. It is, therefore, not surprising that the failure of proteostasis mechanisms underpins the pathogenesis of common diseases of old age, most notably, cancer and neurodegenerative diseases such as Alzheimer's and Parkinson¡¯s disease. In many of such diseases proteins self-assemble in an aberrant manner into large molecular aggregates, including soluble oligomeric species and amyloid fibrils. Arguably, strategies to ameliorate misfolding and aggregation will depend on a detailed understanding of manipulators of the proteostasis network.

The main interest of our lab is to advance our understanding of the molecular events triggered by protein misfolding and the subsequent impact of protein aggregation on cellular integrity. We combine biochemical and molecular biological studies to tackle questions such as: What are the characteristics of aggregated protein species accumulating in vivo? How are specific species toxic to cells? Which cellular mechanisms can be modified to rescue proteostasis? To address these questions we combine protein engineering with the wide range of genetic and molecular techniques available in cell culture and Drosophila melanogaster. We are also very interested in establishing novel experimental tools, which include for example the quantitative analysis of Drosophila models and the in vivo characterisation of protein-protein interactions. Hopefully, understanding the detailed molecular processes leading to protein misfolding will open new routes towards the design and development of rational treatments for these debilitating diseases.