Prion proteins are a common part of cell surface proteins in the mammalian nervous system, and they can, upon change of its conformation, become a highly infectious and pathogenic agent. The physiological form (PrPC) is encoded by the PRNP gene on chromosome 20 and when misfolded and aggregated, the pathological form (PrPSc) occurs, lacking any specific nucleic acid and its primary structure being determined by the PrPC form. When accumulated in the central nervous system (CNS) of mammals, PrPSc is known to be responsible for uprise of several untreatable progressive neurodegenerative diseases, generally called as transmissible spongiform encephalopathies (TSEs). These include kuru, fatal familial insomnia (FFI) and Creutzfeld-Jacob disease (CJD) in humans, bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, transmissible mink encephalopathy (TME) in mink, feline spongiform encephalopathy (FSE) in cat or chronic wasting disease (CWD) in deer and elk [1] [2] [3]
Protein structure
The PrPSc differs from PrPC solely in conformation and is its isoform. The mature PrPC consists of approx. 208 amino acids, arranged as a disordered N-terminus and a globular C-terminal domain consisting of three α-helices and a short, antiparallel β-pleated sheet. [4] [5] There is a GPI membrane anchor at the C-terminus that tethers the protein to cell membranes and proteins that are secreted and lacking the anchor component has been proven to be unaffected by the infectious isoform [6] In contrast to the natural form of prion protein with only about 3 % of β-sheet secondary structure, the PrPSc form has about 47 % of the secondary structure in β-sheets [7] that create a core of four-rung β-solenoid fold [8]. Accordingly, they also differ in their properties. PrPC is soluble, has a life-span between 2 and 4 hours, and is sensitive to proteolytic cleavage – when exposed to proteases, the protein is degraded completely [9]. The two most important cleavage events are the α cleavage which removes the unstructured N-terminal tail and leaves the globular domain attached to the cell membrane, and the cleavage on the C-terminal end (termed PrPC shedding) which releases PrPC into the extracellular space [10]. Under the same conditions, PrPSc is hydrolysed by proteases only partially by forming resistant core fragment PrP 27-30 [11]. In addition, it is insoluble in detergents and has a very long half-life, therefore accumulates in tissues easily. It has a tendency to form aggregates and fibrillar structures and is generally susceptible to oligomerization, whereas the PrPC form mainly exist as a monomer [12]. Monomeric PrPSc has never been isolated.
Misfolding
The fundamental event in propagation of the infectious form lies in the PrPSc template-directed misfolding of the natural form into the pathogenic, β-sheet-rich version of itself [13]. This process is now widely accepted as a current prion theory, and the most striking fact is that this action lacks any nucleic acid template [14]. However, the replication cycle of PrPSc does need the PRNP gene to direct PrPC synthesis. Also, the interaction between the pathogenic and physiological form must be quite specific to propagate the conversion. The replication process itself can be explained by stochastic fluctuations in the PrPC structure, that would create the intermediate form, PrP*. This partially unfolded monomer can then switch back to the natural conformation, adopt a PrPSc one, or be degraded. Normally, there is an equilibrium between the PrPC and PrP* states which favors the physiological one. Depending on the specific cause of the disease, the PrP* state can adopt a PrPSc conformation either upon contant with a dimer of this infectious form by forming a heteromultimer which is further converted into a homomultimer of PrPSc, or through encounter with another PrP* molecule. This PrP*/PrP* dimer can then form an infectious dimer and initiate the replication cycle [15] [16]. It has been found that certain host-specific RNAs can assist with the conversion into the pathogenic form [17]
Pathogenesis
In the case of infectious/iatrogenic diseases, pathogenic prion proteins enter the body alimentary via ingestion of affected neural tissues, or via infected materials and tissues such as during blood transfusions, corneal transplants or dura mater grafts. In this case, the exogenous PrPSc form would serve as a template to promote the conversion of PrP* and, due to its insolubility, make this exponential conversion process irreversible (Cohen et al. 1994).
Genetic, or inherited cause comprise the familial TSEs and comes from DNA mutations in the PRNP gene, which then produces mutant, unstable forms of PrPC with higher tendency of folding into the PrP* form. This further increases the chance of PrPSc forming (Cohen and Prusiner, 2002). The mutations in PRNP are autosomal dominant, highly penetrant, and consist of missense mutations, insertions and deletions (Sigurdson et al., 2019). With higher probability of protein misfolding in the old age, they usually incite disease onset in the late decades of life and ultimately lead to accumulation of prion proteins and rapid development of neurodegenerative disease (Khanam et al. 2016).
Concerning sporadic form of prion disease, the concentration of PrPSc may eventually reach a threshold level upon which a positive feedback loop would stimulate the formation of PrPSc. It requires solely a rare molecular event of formation of the PrP*/PrP* complex, or a somatic cell mutation followed by the mechanism of the initiation of inherited disease. Once formed, the replication cycle is primed for subsequent conversion (Cohen et al., 1994, Cohen and Prusiner, 2002).
Ultimately, in all cases this leads to PrPSc polymerization, forming a rod-like structures and amyloid plaques.
Prion diseases
Diagnosis and treatment
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