Prion diseases or transmissible spongiformencephalopathies (TSEs) are a family of rare progressive neurodegenerativedisorders that affect both humans and animals. They are distinguished by longincubation periods, characteristic spongiform changes associated with neuronalloss, and a failure to induce inflammatory response.
The causative agents of TSEs are believed to be prions.The term "prions" refers to abnormal, pathogenic agents that aretransmissible and are able to induce abnormal folding of specific normalcellular proteins called prion proteins that are found most abundantly in thebrain. The functions of these normal prion proteins are still not completelyunderstood. The abnormal folding of the prion proteins leads to brain damageand the characteristic signs and symptoms of the disease. Prion diseases areusually rapidly progressive and always fatal.
Familial prion diseases of humans include classicCreutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS),and fatal insomnia (FI). These conditions form a spectrum of diseases withoverlapping signs and symptoms.The prevalent controversial ‘protein-only’ hypothesisproposes that the infectious agent is a misfolded protein that triggers andpropagates the disease in the absence of nucleic acid. The prion protein is thecause for all known mammalian prion diseases. Prion proteins are thought toexist in two different conformations. A properly folded form is denoted PrPC(for Common or Cellular)and a misfolded form is denoted PrPSc (for Scrapie,after one of the diseases first linked to prions and neurodegeneration.) Theprecise structure of the prion is not known but it can be formed by combiningPrPC, polyadenylic acid, and lipids in a Protein Misfolding CyclicAmplification (PMCA) reaction.
The protein encoded by the major prion protein gene is amembrane glycosylphosphatidylinositol-anchored glycoprotein that tends toaggregate into rod-like structures. The encoded protein contains a highlyunstable region of five tandem octapeptide repeats. This gene is found onchromosome 20, approximately 20 kbp upstream of a gene which encodes abiochemically and structurally similar protein to the one encoded by this gene.Mutations in the repeat region as well as elsewhere in this gene have beenassociated with Creutzfeldt-Jakob disease, fatal familial insomnia,Gerstmann-Straussler disease, Huntington disease-like 1, and kuru. Alternativesplicing results in multiple transcript variants encoding the same protein.
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