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.