Prion Disorders

Abstract

Prion diseases are neurodegenerative conditions that, in contrast to Alzheimer, Parkinson and other neurodegenerative diseases, are transmissible from one individual to another. The infectious agent causing prion diseases has been proposed to consist exclusively of a protein. The exact mechanism by which the agent replicates is still unclear.

Keywords: prion protein; PrPSc; PrPC; transmissible spongiform encephalopathies; scrapie; protein‐only hypothesis; neuroinvasion; amyloid plaques; microglia; transgenic mice; knockout mice

Figure 1.

Models for the conformational conversion of PrPC into PrPSc. (a) The ‘refolding’ or template assistance model postulates an interaction between exogenously introduced PrPSc and endogenous PrPC, which is induced to transform itself into further PrPSc. A high‐energy barrier may prevent spontaneous conversion of PrPC into PrPSc. (b) The ‘seeding’ or nucleation‐polymerization model proposes that PrPC and PrPSc are in a reversible thermodynamic equilibrium. Only of several monomeric PrPSc molecules are mounted into a highly ordered seed, can further monomeric PrPSc and eventually aggregates of amyloid be recruited. Within such a crystal‐like seed, PrPSc becomes stabilized. Fragmentation of PrPSc aggregates increases the number of nuclei, which can recruit further PrPSc and thus result in apparent replication of the agent.

Figure 2.

Posttranslational processing of PrPC. The coding region of the human PrP gene displaying the N‐ and C‐terminal signal sequences. Upon reaching its destination on the cell surface, an N‐terminal secretory signal peptide of 22 amino acids is cleaved from the 254 amino acid PrPC precursor protein. Twenty‐three C‐terminal residues are also processed during addition of the glycosyl phosphatidylinositol (GPI) anchor to a serine residue at position 231. Upon completion of these modifications, mature PrPC contains 209 amino acids. PrPSc is a modified form of PrPC. PrPC and PrPSc have an identical amino acid sequence and share the same posttranslational modifications, but differ in their secondary and (presumably) tertiary structures. The physiological isoform PrPC is protease‐sensitive, while the pathological isoform PrPSc is partially protease‐resistant, displaying a protease‐resistant core of PrPSc, designated PrP27–30.

Figure 3.

Patterns of PrP glycosylation. Representation of the three glycosylated PrPSc moieties (non‐, mono‐ and diglycosylated PrPSc) in immunoblots of brain extracts after digest with proteinase K. Different inocula result in specific mobilities of the three PrP bands as well as different predominance of certain bands (middle panel). These characteristic patterns can be retained, or changed to other predictable patterns after passage in wild‐type mice (upper panel) or humanized mice (PrP‐deficient mice bearing a human PrP transgene, lower panel). On the basis of the fragment size and the relative abundance of individual bands, three distinct patterns (PrPSc types 1–3) were defined for sporadic and iatrogenic CJD cases. By contrast, all cases of nvCJD displayed a novel pattern, designated a type‐4 pattern.

Figure 4.

Characteristic neuropathologic features of transmissible spongiform encephalopathies. Gray matter of the brain of a CJD patient stained with hematoxylin and eosin (H & E) displaying the characteristic spongiform, vacuole‐like morphology (left). Activation and proliferation of reactive, swollen astrocytes is visualized by staining with antibodies against glial fibrillary acidic protein (GFAP, brown color, middle). Immunohistochemical staining using anti‐PrP antibodies representing prion protein deposits (brown color, right).

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Aguzzi, Adriano(Sep 2005) Prion Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0005170]