Prion proteins diseases

The transmissible spongiform encephalopathies, or prion diseases, are fatal neurodegenerative diseases characterized by spongiform changes, astrocytic gliomas, and neuronal loss resulting from the deposition of insoluble protein aggregates in neural cells. They include Creutzfeldt-Jakob disease in humans, scrapie in... 

Prions—protein particles that lack nucleic acid— cause fatal transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease, scrapie, and bovine spongiform encephalopathy. Prion diseases involve an altered secondary-tertiary strucmre of a namrally occurring protein, PrPc. When PrPc interacts with its pathologic isoform PrPSc, its conformation is transformed from a predominantly a-helical strucmre to the P-sheet strucmre characteristic of PrPSc. 

Burkhard P, Stetefeld J, Strelkov SV Coiled coils A highly versatile protein folding motif. Trends Cell Biol 2001 11 82. Collinge J Prion diseases of humans and animals Their causes and molecular basis. Annu RevNeurosci 2001 24 519. 

Soto C Alzheimer s and prion disease as disorders of protein conformation Implications for the design of novel therapeutic... 

Prion diseases resulting in encephalopathy can be transmitted between individuals within species (more rarely between species) [26-28], A conformational variant of the normal cellular protein PrPs (PrPc) (protease-sensitive or cellular) is believed to catalyze [29] or nucleate [30-33] conversion to the pathological form, PrPR (protease-resistant). This highly unusual nongenetic mode of transmission of an infectious agent has been strongly debated [29]. The observation of multiple examples of nucleated catalysis of aberrant polymerization of protein subunits has... 

Kellershohn N, Laurent M. Species barrier in prion diseases a kinetic interpretation based on the conformational adaptation of the prion protein. Biochem J 1998 334 539-545. 

The conformational plasticity supported by mobile regions within native proteins, partially denatured protein states such as molten globules, and natively unfolded proteins underlies many of the conformational (protein misfolding) diseases (Carrell and Lomas, 1997 Dobson et al., 2001). Many of these diseases involve amyloid fibril formation, as in amyloidosis from mutant human lysozymes, neurodegenerative diseases such as Parkinson s and Alzheimer s due to the hbrillogenic propensities of a -synuclein and tau, and the prion encephalopathies such as scrapie, BSE, and new variant Creutzfeldt-Jacob disease (CJD) where amyloid fibril formation is triggered by exposure to the amyloid form of the prion protein. In addition, aggregation of serine protease inhibitors such as a j-antitrypsin is responsible for diseases such as emphysema and cirrhosis. 

Aberrant metabolism of the prion protein is the central feature of prion diseases 792... 

Pathogenic mutations in the prion protein gene cause inherited prion disease 793... 

Acquired human prion diseases include kuru and variant CJD 794 Prion protein polymorphism contributes genetic susceptibility to prion disease 794... 

All three of these predictions from this minimal model are manifest in the etiology of prion disease an inversely proportional relationship between PrPc expression and prion incubation period in transgenic mice predisposition by relatively subtle mutations in the protein sequence and a requirement for molecular homogeneity between PrPSc and PrPc for efficient prion propagation [4, 5, 20]. It is clear that a full understanding of prion propagation will require knowledge both of the structure of PrPc and PrPSc and of the mechanism of conversion between them. 

Collinge, J. et al. Presymptomatic detection or exclusion of prion protein gene defects in families with inherited prion diseases. Am. J. Hum. Genet. 49 1351-1354,1991. 

Horwich, A. L., and Weissman, J. S. (1997). Deadly conformations—protein misfolding in prion disease. Cell 89, 499-510. 

With the background of the mad cow crisis in Europe, questions relating to the prion diseases have attracted intensive interest. It is now widely accepted that prion diseases, such as Creutzfeldt-Jakob disease (CJd) in humans and bovine spongiform encephalopathy (BSE) are caused by a conformational change of the prion protein (PrP) from a normally folded cellular form, PrP ", to an alternate, aggregation-prone, pathogenic scrapie form,... 

Protein aggregation is a hallmark of scrapie, and scrapie protein can be induced to aggregate in vitro into forms that are indistinguishable from pathological brain-derived fibrils. Prusiner proposed that prion disease involves a mechanism for autocatalytic conversion of a host... 

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