Redox signalling by the cellular prion protein (PrPC) and its role in the cellular calcium homeostasis

• Applicant: Professor Dr. Jochen W. Herms
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2005 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5455719

The cellular prion protein (PrPC) is thought to be involved in protection against cell death, however the exact cellular mechanisms responsible are still controversial. Previous data of the applicant strongly indicate a functional link between PrPC expression and phosphatidylinositol 3-kinase (PI3-kinase) activation, a protein kinase that plays a pivotal role in cell survival. PI3-kinase activity was found to be reduced in brain lysates from prion protein knockout mice. Activation of PI3- kinase by PrPC was shown to contribute to cellular survival toward oxidative stress. Moreover, both PI3-kinase activation and cytoprotection by PrPC appeared to rely on copper binding to the N-terminal octapeptide of PrPC. The present application aims to analyse the link between PrPC, the PI3-kinase cascade and survival more closely. First, we want to identify the biochemical redox activity of PrPC that relates to PI3-kinase activation. Secondly, we will study the PrPC-dependent mechanisms that mediate transmembrane signaling. Thirdly, we aim to elaborate the PrPC-dependent survival cascade both upstream and downstream of PI3-kinase, with particular focus on the mitochondria.

• DFG Programme: Research Grants