Neurotoxicity of a mutant prion protein

Prion diseases are transmissible neurodegenerative disorders featuring a unique infectious agent, the prion. This molecule is composed primarily of PrP Sc, a misfolded conformer of a normal cell-surface glycoprotein, the cellular prion protein or PrP C. The mechanisms by which prions cause neuronal death are still poorly understood. All evidence points towards the possibility that the physiological activity of PrP C is in some way necessary for prion- induced neurotoxicity. An intriguing hypothesis is that PrP C normally exerts a neuroprotective function that is subverted by PrP Sc (or PrP toxic, a putative toxic form of the prion protein that may be distinct from PrP Sc). To further elucidate a possible subversion of normal PrP C function, a transgenic mouse model expressing PrP with a deletion of a conserved block of 21 amino acids (residues 105-125) in its central region was created. This region is thought to constitute a critical determinant of the neurotoxic and neuroprotective properties of the prion protein. In the absence of endogenous PrP, the animals develop a severe neurodegenerative illness only few days after birth, and die within one week. Neuropathologically, symptomatic transgenic mice show marked cerebellar atrophy with dramatic granule cell loss. The phenotype is ameliorated, but never completely abolished, by coexpression of wild- type PrP. The massive neurotoxic effect of the mutant PrP could be explained by aberrant binding to a hypothetical receptor, which then transduces a neurotoxic rather than - as in the physiological situation, with binding of PrP C - a neuroprotective signal. This subversion of function might occur because delivery of a neuroprotective signal requires binding of PrP to the receptor at two distinct sites, namely the 105-125 region and the C-terminal domain of the protein. If the 105-125 region is absent, binding of the C-terminal domain alone could produce a neurotoxic signal. The present project is directed at clarifying the exact mechanism of cell death in cerebellar granule neurons of the previously established transgenic mouse model. The identification of signaling pathways involved in granule cell degeneration is expected to provide important informations about the nature of the proposed binding partner of PrP, as well as of the interaction between the two molecules. Our model, which defines the 105-125 region as a pivotal functional domain of PrP that determines its neurotoxic and neuroprotective activities, does not only provide insights into the physiological function of the prion protein, but could also explain how this function may be subverted in prion diseases. There, PrP Sc or other toxic forms of PrP might perturb interaction between PrP C and a putative receptor by blocking binding within the 105-125 domain, thereby producing a toxic signal equivalent to that elicited by the mutant PrP missing that domain. In the absence of PrP C, no signal would be delivered, and no prion-induced pathology could develop.