Project 171139

Prion diseases or transmissible spongiform encephalopathy (TSEs) are characterized by protein aggregation and neuronal degeneration. They affect diverse mammals including bovines (bovine spongiform encephalopathy, BSE) and humans (e.g. Creutzfeldt-Jakob disease). BSE is an important health and economical concern in Canada, due to its potential to affect the food supply and be transmitted to humans. Furthermore, the risks related to iatrogenic contamination by blood transfusion have been recently recognized. Unfortunately, therapeutic interventions in prion diseases are elusive; TSEs are still incurable and fatal. Prion infection and pathology requires the expression of a host prion protein, PrPC. The latter is co-opted by prions to convert into an abnormal insoluble form, PrPSc, with possible gain of neurotoxic activity. However, several evidences suggest that this model might be too simplistic. For example, clinical manifestations in TSEs may occur either before or without PrPSc deposits, so it is also plausible that loss of normal functions of PrPC may contribute to pathogenesis. The identification of PrPC functions is pivotal for understanding TSEs. Strong evidence for PrPC physiological functions derives from previous description of its association with the Stress Inducible Protein 1 (STI1). Recently, it has been demonstrated that STI1 is secreted by astrocytes. STI1 can protect neurons by binding to PrPC and increasing PKA activity. Moreover, STI1-PrPC interaction evokes neuritogenesis via activation of ERK 1/2. We hypothesized that STI1-PrPC engagement triggers neurotrophic-like actions that may have fundamental roles in the nervous system. Hence, in order to test this hypothesis and characterize possible PrPC loss-of-function mechanisms in TSEs, we will use a combination of techniques to define pathways involved with STI1 secretion, PrPC transduction of cellular signals and to disturb STI1-PrPC interaction in vivo.

investigating the neurotrophic functions of the cellular prion protein (PrPC) and its interaction with the Stress Inducible Protein 1 (STI1)