Abstract
The human cellular prion protein (PrPC) is a glycosylphosphatidylinositol (GPI) anchored membrane glycoprotein with two N-glycosylation sites at residues 181 and 197. This protein migrates in several bands by Western blot analysis (WB). Interestingly, PNGase F treatment of human brain homogenates prior to the WB, which is known to remove the N-glycosylations, unexpectedly gives rise to two dominant bands, which are now known as C-terminal (C1) and N-terminal (N1) fragments. This resembles the β-amyloid precursor protein (APP) in Alzheimer disease (AD), which can be physiologically processed by α-, β-, and γ-secretases. The processing of APP has been extensively studied, while the identity of the cellular proteases involved in the proteolysis of PrPC and their possible role in prion biology has remained limited and controversial. Nevertheless, there is a strong correlation between the neurotoxicity caused by prion proteins and the blockade of their normal proteolysis. For example, expression of non-cleavable PrPC mutants in transgenic mice generates neurotoxicity, even in the absence of infectious prions, suggesting that PrPC proteolysis is physiologically and pathologically important. As many mouse models of prion diseases have recently been developed and the knowledge about the proteases responsible for the PrPC proteolysis is accumulating, we examine the historical experimental evidence and highlight recent studies that shed new light on this issue.
Highlights
IntroductionTransmissible spongiform encephalopathies (TSE diseases) or prion diseases are all fatal neurodegenerative conditions that include scrapie in sheep, bovine spongiform encephalopathy (BSE)
Transmissible spongiform encephalopathies (TSE diseases) or prion diseases are all fatal neurodegenerative conditions that include scrapie in sheep, bovine spongiform encephalopathy (BSE)in cattle, chronic wasting disease (CWD) in cervids, and kuru, Gerstmann-Sträussler-Scheinker syndrome (GSS), sporadic, familial, and variant forms of Creutzfeldt-Jakob disease (CJD) in humans.The central dogma of prion biology is that the normal cellular isoform of prion protein (PrPC) encoded by the highly conserved single-copy gene Prnp [1] is post-translationally refolded into a partially protease resistant and -sheet-enriched conformation that is infectious [2].neither the mechanism by which PrPSc causes neuronal dysfunction during prion disease nor the normal function of PrPC is well defined
This hydrophobic core (HC) region is immediately adjacent to the putative cleavage site of PrPC, which is enriched in charged residues (Figure 1), designated the charged cluster (CC) region
Summary
Transmissible spongiform encephalopathies (TSE diseases) or prion diseases are all fatal neurodegenerative conditions that include scrapie in sheep, bovine spongiform encephalopathy (BSE). When Wilfried W. de Jong’s group compared PrP coding sequences in 26 mammalian species [18], they noted that a hydrophobic region in the middle of PrPC is perfectly conserved, suggesting that the region is functionally important for PrPC This hydrophobic core (HC) region is immediately adjacent to the putative cleavage site of PrPC, which is enriched in charged residues (Figure 1), designated the charged cluster (CC) region. One product is a secreted form of full-length PrPC, which is released from the membrane when the GPI-anchor is cleaved They found a second truncated form that accounts for most of the surface-anchored molecules in transfected murine cells, indicating that the machinery to generate C1 is highly conserved between species. Physiological anchorless prion protein may exist in humans due to alternative splicing of exon 2 of the PrP gene, which eliminates the GPI-anchor [23] (see Figure 1). None of the physiological functions of all these prion proteins has so far been clarified
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