Prion Protein


Prion diseases belong to the group of lethal neurodegenerative diseases. Histopathologically, they are characterized by spongiform degeneration of brain tissue and accumulation of amyloid protein plaques, leading to neuronal cell death. In contrast to other neurodegenerative diseases like Parkinson or Alzheimer, prion diseases feature an infectious character with a misfolded isoform of the ubuquitously expressed cellular prion protein (PrPSc) as the pathogenic agent. According to the generally accepted protein-only hypothesis, the autocatalytic misfolding of the cellular prion proteins is considered as the fundamental event of pathogenisis which is subsequently followed by aggregation of PrpSc molecules leading to amyloid plaque formation.
The structure of the prion protein is composed of an unfolden N-terminal part followed by a well-folded globular C-terminal part with three dominating α-helices and a short antiparallel β-sheet. After rearrangement of the folding the PrpSc isoform mainly consists of β-sheet structures which is considered to be the reason for aggregation and high resistance against proteinase K cleavage. The physiological role of the prion protein has not been fully clarified until now. However, strong evidence for involvement of the prion protein in cellular defense mechanisms against oxidative stress has been accumulated during the last years. By in vitro experiments it could be confirmed that the specific change of folding and subsequent aggregation of prion proteins can be induced by oxidation of defined amino acids. A potential influence of the Cu(II)-coordination on oxidative processes is presently matter of controversial discussions.
A detailed understanding of the conformational changes and following aggregation of the prion protein is crucial for the development of effective therapeutics against this disease. Especially, the potential transfer of results to other protein misfolding diseases clearly illustrates the relevance of prion-based research. The aim of the SIAS group therefore is the investigation of the dynamic conformational changes of the prion protein based on the previous knowledge and well-established oxidative in vitro assays.


Contact person for this project: Anne Sommer