Final Report Summary - PRIONS (The prion protein in health and disease)
The prion protein, PrP, exists in two main forms: the cellular, normally folded version, PrPC, and the misfolded version, generally referred to as PrPSc, which is main if not the solely components of prions, the infectious agents causing prion diseases. These are devastating transmissible neurodegenerative disorders for which no efficacious therapy exists so far. The mechanisms, by which prions kill neurons, as well as the physiological function of the prion protein in its normal conformation, are poorly understood.
Our studies during the ERC-funded research, resulted in important discoveries which significantly contributed at clarifying the role of the prion protein in both physiological and disease states.
We identified an authentic physiological function of PrPC as crucial signaling molecule from axons to Schwann cells for myelin maintenance in the peripheral nerves and we have now gathered exciting results suggesting that the PrP signaling pathway may represent a new therapeutic target in peripheral neuropathies. Parallel to this, we “demystified” some of the alleged immunomodulatory functions of PrPC, including inhibition of phagocytosis.
We have invented a unique, faithful ex vivo model to study prion-induced neurodegeneration: the prion organotypic slice culture assay (POSCA). Because cultured cells do not experience prion-induced cell death, the study of prion toxicity was only possible using animals – which created problems of pharmacological accessibility and of animal welfare. The method which we have invented overcomes all of these issues. We are currently taking advantage of these new developments for large genetic and pharmacological screens. Combining the organotypic slice culture system and our set of specific anti-PrP antibodies, we identified the flexible tail FT of PrPC as the allosteric effector of prion toxicity and we pointed out the misfolded PrP-mediated neurotoxic signaling pathways - which include ROS production and calpain activation. Prions kill neurons but also dramatically affect the other cellular populations - such as astrocytes and microglia - in the brain parenchyma. The role played by these cells and their changes in prion pathogenesis are not clear. We were able to dissect the dual impact of microglia in tuning PrPSc mediated neurotoxicity: its activation in prion infection enhances prion clearance and, on the other side, overactivation of NOX2 in microglia significantly contributes to prion-induced neurotoxicity.
We determined the role of PrPC in other PMA disorders by studies in vivo. It had been suggested that the prion protein was a mediator of Abeta amyloid dependent neurotoxicity thus participating to the development of Alzheimer’s disease (AD) pathology. We confirmed the ability of PrPC to interact with Abeta oligomers, but, by performing careful genetic analyses on animal models of AD, we demonstrated in vivo that PrPC do not significantly modulate the detrimental effects of Abeta oligomers on hippocampal synaptic plasticity. Our findings challenge the issue about targeting PrPC as a potential therapeutic approach to treat AD.
Our studies during the ERC-funded research, resulted in important discoveries which significantly contributed at clarifying the role of the prion protein in both physiological and disease states.
We identified an authentic physiological function of PrPC as crucial signaling molecule from axons to Schwann cells for myelin maintenance in the peripheral nerves and we have now gathered exciting results suggesting that the PrP signaling pathway may represent a new therapeutic target in peripheral neuropathies. Parallel to this, we “demystified” some of the alleged immunomodulatory functions of PrPC, including inhibition of phagocytosis.
We have invented a unique, faithful ex vivo model to study prion-induced neurodegeneration: the prion organotypic slice culture assay (POSCA). Because cultured cells do not experience prion-induced cell death, the study of prion toxicity was only possible using animals – which created problems of pharmacological accessibility and of animal welfare. The method which we have invented overcomes all of these issues. We are currently taking advantage of these new developments for large genetic and pharmacological screens. Combining the organotypic slice culture system and our set of specific anti-PrP antibodies, we identified the flexible tail FT of PrPC as the allosteric effector of prion toxicity and we pointed out the misfolded PrP-mediated neurotoxic signaling pathways - which include ROS production and calpain activation. Prions kill neurons but also dramatically affect the other cellular populations - such as astrocytes and microglia - in the brain parenchyma. The role played by these cells and their changes in prion pathogenesis are not clear. We were able to dissect the dual impact of microglia in tuning PrPSc mediated neurotoxicity: its activation in prion infection enhances prion clearance and, on the other side, overactivation of NOX2 in microglia significantly contributes to prion-induced neurotoxicity.
We determined the role of PrPC in other PMA disorders by studies in vivo. It had been suggested that the prion protein was a mediator of Abeta amyloid dependent neurotoxicity thus participating to the development of Alzheimer’s disease (AD) pathology. We confirmed the ability of PrPC to interact with Abeta oligomers, but, by performing careful genetic analyses on animal models of AD, we demonstrated in vivo that PrPC do not significantly modulate the detrimental effects of Abeta oligomers on hippocampal synaptic plasticity. Our findings challenge the issue about targeting PrPC as a potential therapeutic approach to treat AD.