Prions Proteins

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Prions Proteins

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Prions Proteins Background

Prion-mediated disorders are a class of incurable neurodegenerative diseases. These disorders involve the misfolding of the cellular prion protein (PrPC) into an aberrant scrapie form (PrPSc), causing the accumulation of PrPSc in neurotoxic oligomers that eventually lead to patient death.

The cellular prion protein is a glycophosphatidylinositol (GPI)-anchored cell surface glycoprotein that is highly conserved in mammals. Paralogues can also be found in numerous organisms, including zebrafish, turtles, and other amphibian species. In mammals, PrP is widely expressed in multiple tissues, but predominantly on the synaptic membrane of neurons and their associated cells (such as astrocytes and Schwann cells) as well as in heart, muscle, and hematopoietic cells.


Structure of prion protein

Mammalian prions (notably mouse, human, cattle, and hamster PrP) share common structural features and contain roughly 208 aa in their mature form. At the N-terminus of the protein, an ER-targeting signal sequence is cleaved following translocation under normal conditions and comprises the first 22 amino acids. Immediately downstream is a charged cluster composed of the first nine residues of the mature domain (aa 23 to 31, human numbering), followed by a long, flexible N-terminal tail (aa 32-128) that encompasses roughly half of the protein and is mostly disordered, except for two defined regions. The first region consists of five repeats of a conserved histidine-containing octameric sequence spanning residues 51 to 91. It has been shown to be responsible for PrPC’s copper-binding properties, whereas PrPSc does not bind copper. In addition, copper upregulates the expression of PrP in neurons. Although the physiological role of PrP’s copper-binding abilities remains unknown, PrP was shown to be evolutionary descended from the ZIP family of metal ion transporters. The second region is a hydrophobic domain located between residues 112 and 135 that can under particular conditions act as a transmembrane domain.

Further downstream are three α-helices and a double-stranded β-sheet forming the globular C-terminal half of PrPC. Additionally, a disulphide bond links helices two and three at positions 179 and 214, stabilising the C-terminus of the protein. Two N-linked glycosylation sites (aa 181 and 197) are inefficiently used, resulting in a mixed PrP population with zero, one, or two glycan chains and causing a characteristic banding pattern as detected by western blot. Finally, the GPI signal peptide is found at the C-terminal end of the primary sequence (aa 231-254) and allows PrP to be bound by a GPI anchor.

Linear and three-dimensional structure of PrPC..png

Fig. 1 Linear and three-dimensional structure of PrPC.


Physiological Functions of prion protein

Although a great number of putative PrPC functions have been proposed, there is no consensus on its physiological role. Generally, PrP appears to be dispensable in mammals. PrP-/- mice, goats, and cattle show only mild phenotypes, such as a slight increase in the locomotor activity of PrP-/- mice during exploration of a new environment or a minor decrease in the myelin sheath of neurons. However, PrP-/- zebrafish embryos are unable to progress past gastrulation due to loss of embryonic cell adhesion, which posits a possible role in development. This hypothesis is also supported by the discovery that the transcription of the Prnp gene in mouse embryos is triggered at different time points in different tissues. PrP has also been implicated in memory formation, notably in long-term potentiation and synaptic plasticity by controlling the activity of protein kinase A in synapses. To further support this, PrP is abundantly expressed in the hippocampus, a brain region which plays an important role in both short- and long-term memory consolidations. One of the other few differences between wild-type and PrP-/- mice is that the knock out animals are more susceptible to strokes and ischemic damage. This may be due to their lower levels of phosphorylated Akt, which suggests that PrP may be involved in the activation of cell survival pathways. However, there is no dearth of contradicting evidence as PrP-/- mice do not display any learning or cognitive impairment compared to wild-type control animals. Moreover, crossing PrP-/- mice with transgenic mouse models of several neurodegenerative disorders (Alzheimer’s, Huntington’s, and Parkinson’s diseases; AD, HD, and PD respectively) did not alter the phenotypes exhibited by the animals, showing the limitations of PrPC’s putative neuroprotective effect.

In addition, a substantial body of evidence implicates a role for PrP in AD, but there is also an abundance of contradictory evidence. On the one hand, PrPC has been identified as the receptor for Aβ oligomers and may mediate the neurotoxic effects caused by these oligomers, although this last point is controversial. On the other hand, PrPC has been shown to downregulate the activity of β-site APP-cleaving enzyme 1 (BACE1), which is responsible for the conversion of amyloid precursor protein (APP) into the aggregation-prone, neurotoxic Aβ. Furthermore, certain PrPC cleavage fragments have been shown to harbor neuroprotective properties. For instance, cleaved fragment N1 may inhibit the oligomerisation of Aβ peptides, suppressing their neurotoxic effects.


Neurodegenerative Prion Disorders

Transmissible spongiform encephalopathies (TSEs) are a group of invariably fatal neurodegenerative diseases that feature the irreversible misfolding of the cellular prion protein (PrPC) into its scrapie form (PrPSc). They cause a severe loss of motor and cognitive skills in the victim and, often, behavioral changes. One of the pathohistological hallmarks of these diseases is neuronal death, eventually causing the brain’s appearance to be reminiscent of that of a sponge (hence spongiform). These disorders affect many mammals, including humans, sheep, cows, deer, and elk and can be classified in three distinct classes: sporadic, transmissible, and familial.

Sporadic diseases represent 85% of the reported cases in humans, and are due to the spontaneous misfolding of PrP without prior exposure to exogenous PrPSc or inherited genetic mutations. The most common one is sporadic Creutzfeldt-Jakob disease (CJD), which is still rare with a worldwide lifetime incidence of 1 in 2 million people. In all sporadic instances of prion disorders, the aberrant scrapie prions may be disease-causing in healthy individuals. The two main polymorphisms in PrP result in one of two amino acids at position 129, namely methionine or valine. In Caucasians, 51% of the population is heterozygous, 37% Met homozygous, and 12% Val homozygous. Although no mechanistic link has been found between CJD and PrP polymorphisms, heterozyosity at codon 129 appears to diminish the risk associated with that disease.

Familial cases are less common, representing 10 to 15% of the cases of human TSEs. One such disease is fatal familial insomnia (FFI), which affects fewer than 40 families and 100 patients. Other than the usual TSE-associated loss of cognitive and motor skills, affected individuals suffer from a progressively worsening inability to attain sleep, and finally pass away an average of 18 months after onset. Another inheritable disease is the Gerstmann–Sträussler–Scheinker syndrome (GSS), which is very similar to CJD in its symptoms but distinct at the pathohistological level as it affects different regions of the brain. On their own, neither methionine nor valine at codon 129 is disease-causing; however, they determine the pathology caused by the mutation D178N. Indeed, the 129Met D178N haplotype leads to FFI, whereas 129Val D178N causes familial Creutzfeldt-Jakob disease (fCJD).

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