Searching for Reliable Premortem Protein Biomarkers for Prion Diseases

Progress and Challenges to Date

Di Ma; Lingjun Li


Expert Rev Proteomics. 2012;9(3):267-280. 

In This Article

Prion Diseases & Prion Protein

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a unique family of fatal neurodegenerative diseases that affect both animals and humans. Depending on the animal host, prion diseases, include scrapie, which has been known for more than 200 years to affect the nervous system of sheep and goats; the one most recently recognized is bovine spongiform encephalopathy (BSE or 'mad cow disease') among cattle and chronic wasting disease (CWD) in deer. Human prion diseases are classified into the following four types: Kuru, which was the first known human TSE found among the Fore people in the highlands of New Guinea that resulted from the practice of ritualistic cannibalism,[1] Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia and Creutzfeldt–Jakob disease (CJD). CJD has also been classified into four distinct forms: classic or sporadic (sCJD), genetic (gCJD), variant (vCJD) and iatrogenic CJD (iCJD).

The infectious agent in prion diseases is prion protein. It is capable of introducing the conversion of normal host cellular prion protein (PrPC) into the abnormal protease-resistant isoform (PrPSc), which has a higher proportion of β-sheet structures in place of the normal α-helix structures.[2,3] PrPC is a 33–35-kDa protein of 253 amino acids encoded by a single copy gene PRNP.[4,5] Molecular genetic studies of prion disease revealed point mutations, insertions and deletions in PRNP and the resulting amino acids change could result in changes to the genetic factors that cause PrPC to be more likely to change spontaneously into the abnormal PrPSc form in genetic prion diseases such as the Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia and CJD.[6,7] Previous studies have identified more than 30 mutations in PRNP, and it has been shown that a common coding polymorphism at codon 129 of PRNP between methionine and valine has a critical role in the susceptibility of prion diseases.[8–10] In contrast, acquired forms of prion disease are transmitted by ingestion of, or exposure to, contaminated biological material via food or during medical procedures. Prion diseases usually progress rapidly and are always fatal. When the normal prion protein converts to the infectious form, the incubation period can vary from months to decades during which time no symptoms are exhibited. Following the onset of symptoms, however, disease progresses rapidly, leading to brain damage and, ultimately, death. Currently, no effective measures of treatment exist for prion diseases. Some chemical compounds that exhibit antiprion properties were used in clinical trials to treat CJD patients. However, these compounds were only effective if administered at the early stage of the disease.[11] Furthermore, issues such as low bioavailability, blood–brain permeability and high toxicity compounded the difficulty of developing effective drugs against prion diseases.[12]

After an outbreak of BSE that occurred among cattle in many European countries in the 1990s, prion diseases attracted attention not only because of the enormous economic losses caused by the slaughtering of cattle and animals linked to positive BSE cattle, but also because of scientific evidence that showed BSE had been transmitted to humans through the consumption of the BSE-contaminated food products.[13,14] Moreover, transmission from humans to humans (iatrogenic transmission) can occur via contaminated surgical equipment, the use of human growth hormone derived from cadaveric pituitaries, and transplantation of corneas and dura mater from infected patients, as well as through blood or blood products.[15,16] It was reported that human-adapted prions are more readily transmitted from human to human via blood transfusion than through ingestion of BSE prions from contaminated meat products.[17]


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