Cellular and molecular mechanisms of prion protein function

• Applicant: Professor Dr. Edward Málaga-Trillo, Ph.D.
• Subject Area: Developmental Neurobiology
• Term: from 2009 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 153560211

Prion proteins (PrPs) are well known for the central role they play in neurodegenerative diseases, yet their physiological function remains poorly understood despite numerous studies carried out in knockout mice. Using knockdown approaches in the zebrafish, we have shown that PrP can modulate E-cadherin-based cell adhesion and actin cytoskeletal dynamics, thereby controlling essential morphogenetic cell movements in the early embryo. These activities depend on the formation of PrP homophilic interactions at cell-cell contacts, and subsequent intracellular signaling via Src-related kinases. Here we propose to further identify and dissect the molecular mechanisms of PrP function during early zebrafish embryogenesis. We will begin by examining the ability of PrP to generate intracellular signals via its GPI membrane anchor. We will then set out to identify the signal transduction mechanisms activated by PrP, particularly those involving Src-related kinases, protein tyrosine phosphatases (PTPs), and small GTPases. Since these molecules are also known to transduce signals generated by receptor tyrosine kinases (RTKs), we will explore the potential interplay between PrP and RTKs such as EGFR and PDGFR. We also aim to establish how exactly these signaling pathways control the activity of Ecadherin adhesion complexes. Finally, we will analyze the effect of PrPassociated signaling on cell morphology, polarity, and motility, in primary culture and directly in the embryo. These cell biological studies will be carried out as a first step towards testing the hypothesis that prion-induced neurodegeneration results from failure by the prion protein (PrP) to provide a yet uncharacterized neuroprotective signal in the brain.

• DFG Programme: Research Grants