Cellular mechanisms of prion-mediated neurodegeneration

The prion diseases are a group of rare but fatal diseases of the central nervous system (the brain in particular) for which there is at present no cure. They include CJD in humans, and scrapie and BSE in animals. These diseases can be acquired by ingestion of foodstuff containing the causative agent (called prion), for example contaminated meat and bone meal in the case of BSE, and products derived from cattle suffering from BSE in the case of variant CJD (vCJD). The BSE epidemic in the UK and the subsequent emergence of vCJD has made prion diseases a subject of intense research. BSE has no doubt transmitted to humans, but what is not known is what proportion of the exposed population will go on to develop vCJD. It is known that vCJD prions are transmitted by blood transfusion and currently there is concern that many of the UK population may be carrying vCJD prions which then may be transmitted through surgical procedures or blood transfusion. How prions cause damage to the nervous system is not known and the work in this study seeks to understand this. Once the key pathways have been defined then new drugs may be developed that act against those pathways. Other more common dementias such as Alzheimer?s disease and Parkinson?s disease may also share similar pathways to nerve cell death so understanding prion disease may also help identify treatment targets for these diseases.

Prion diseases are fatal neurodegenerative disorders whose pathogenesis is associated with a conformational rearrangement of the normal cellular prion protein (PrPC) to abnormal conformers (PrPSc). How prions cause neuronal death is not known. We have recently published in vivo and in vitro experimental data suggesting a novel mechanism for intracellular neurotoxicity mediated by oligomers of misfolded PrP. This grant seeks funding to continue this work to unravel the pathways of prion protein trafficking and degradation and how these may be altered to result in prion-mediated neurotoxicity. Understanding the cellular pathways of prion protein trafficking is fundamental to address how the misfolded prion protein causes neuronal dysfunction and death. We will also study prion neurobiology in our novel vCJD prion propagating cell line and determine the time course of prion degradation and prion-mediated neurodegeneration in ageing human neurons. Following these pathways in a neuronal model close to the human in vivo situation will have clear benefits for the development of therapeutics aimed at enhancing degradation or clearance of human vCJD prions. This cell line will therefore also be useful for screening human prion therapeutics as to date no human cell models exist in which to screen human prion therapies. Understanding cellular mechanisms of neurodegeneration is of fundamental scientific interest and importance. Neurodegenerative diseases represent one of the biggest health problems in our ageing society, and uncovering basic molecular mechanisms is fundamental for the development of rational therapeutics. Many neurodegenerative diseases such as AD, PD and HD occur as a result of misfolding and aggregation of key cellular proteins (protein conformational disorders). Prion disease is the prototypical protein misfolding neurodegenerative disorder as its pathogenesis is only associated with aberrant misfolding of a host cellular protein (the protein-only hypothesis). Therefore, advances in understanding the pathophysiology of prion disease has major implications for other neurodegenerative diseases associated with protein misfolding as it may help elucidate common cellular mechanisms in neurodegeneration. In addition, although prion diseases are rare, there are currently significant public health concerns in the UK re secondary transmission of vCJD (the human form of BSE) and whether a significant number of the UK population are indeed subclinical carriers of prion disease. Therefore the work in this project will both have relevance for the understanding of neurodegeneration per se as well as yield new cellular models for screening of human prion therapeutics.