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The production of transgenic mice expressing different forms of the prion protein (PrP) or devoid of PrP has enabled researchers to study the role of PrP in the infectious process of a prion disease and its normal function in the healthy individual. A wide range of transgenic models have been produced ranging from PrP null mice, normal expression levels to overexpression models, models expressing different species of the Prnp gene and different mutations and polymorphisms within the gene. Using this range of transgenic models has allowed us to define the influence of PrP expression on disease susceptibility and transmission, assess zoonotic potential, define strains of human prion diseases, elucidate the function of PrP, and start to unravel the mechanisms involved in chronic neurodegeneration. This chapter focuses mainly on the use of the gene targeted transgenic models and summarizes the ways in which they have allowed us to study the role of PrP in prion disease and the insights they have provided into the mechanisms of neurodegenerative diseases., (© 2017 Elsevier Inc. All rights reserved.)

Chronic neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs) or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a "prion-like mechanism" is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases.