5. The Aggregation-prone Prion Protein: Normal Function and Expression
Central to prion disease pathology are the conformational changes of the normal prion protein (PrP) isoform, PrPC, which is located primarily on the surface of nerve cells. Conformational changes on the tertiary structure of PrPC result in the infectious form of the protein, also referred to as the misfolded isoform PrPSC (SC stands for “scrapie,” the prion disease that occurs in sheep). These misfolded proteins aggregate into long fibrils and deregulate normal functioning of the brain, leading to prion-related disease such as scrapie, Alzheimer’s disease (AD), and several others [40]. The non-infectious form PrPC, under non-pathogenic conditions, plays many beneficial cellular roles. It participates in lymphocyte activation, cellular differentiation, neurite outgrowth, synaptogenesis, cellular signaling and viability, cellular adhesion processes and many other important functions for cellular homeostasis (for review see Castle AR and Gill AC 2017 [41]).
Overall, PrPC is a stress-induced protein offering cellular protection under stress conditions, and its normal level is increased under conditions of hypoglycemia, ischemia, and in the presence of insulin. Some of the many beneficial roles of PrP and also of β-amyloid precursor protein (APP), which is linked to Alzheimer’s disease, are presented in Table 1. The expression of PrPC is subject to a plethora of transcription factors that are elevated by stress-inducing cellular conditions.
Endoplasmic reticulum stress also induces PrPCexpression, as shown in Table 1 [41]. The Prion Protein gene (PRNP ), although it may be regarded as a housekeeping gene, has multiple binding sites for transcription factors in its promoter region, including the selective promoter factors Sp1 and Sp2, normally known for their tumorigenicity potential [42].
    Table 1. Some of the normal prion protein and β-amyloid precursor protein physiological     functions.