Mutant prion proteins expression in astrocytes: Roles and Impact.

Abstract

Prions, the agents of transmissible spongiform encephalopathies, require the expression of a cellular homologue (PrPc) to propagate disease. The last is converted into an abnormal insoluble form, PrPsc, which a possible gain of neurotoxic activity. Since clinical manifestations may occur either before or without PrPsc deposits, it has been suggested that loss-of PrPc function may concur for disease's etiology. The identification of the PrPc physiological functions is pivotal to understand prion diseases and PrPc mutated proteins associated to genetic forms of these diseases are the best model to understand the loss-of-function component.PrPc is involved in protection against oxidative stress, neuronal adhesion, survival and neurite growth by its interaction with Cu2+, STI-1, laminin and vitronectin. The PrPc expression is also important to modulate astrocytes' proliferation, differentiation and survival. Additionally, the presence of PrPc in astrocytes is critical for sustaining cell-to-cell interactions, the organization of the extracellular matrix, and the secretion of soluble factors, all of which are essential events for neuronal differentiation and survival. The present proposal aims at testing for physiological roles of PrPc in astrocytes, and how these features are altered in mutated PrPc proteins associated with genetic forms of human prion diseases.