Identification of Misfolded Proteins in Body Fluids for the Diagnosis of Prion Diseases

Transmissible spongiform encephalopathy (TSE) or prion diseases are fatal rare neurodegenerative disorders affecting man and animals and caused by a transmissible infectious agent. TSE diseases are characterized by spongiform brain lesions with neuronal loss and the abnormal deposition in the CNS, and to less extent in other tissues, of an insoluble and protease resistant form of the cellular prion protein ( ), named . In man, TSE diseases affect usually people over 60 years of age with no evident disease-associated risk factors. In some cases, however, TSE diseases are unequivocally linked to infectious episodes related to the use of prion-contaminated medicines, medical devices, or meat products as in the variant Creutzfeldt-Jakob disease (CJD). Clinical signs occur months or years after infection, and during this silent period , the only reliable marker of infection, is not easily measurable in blood or other accessible tissues or body fluids causing public health concerns. To overcome the limit of detection, several highly sensitive assays have been developed, but attempts to apply these techniques to blood of infected hosts have been unsuccessful or not yet validated. An update on the latest advances for the detection of misfolded prion protein in body fluids is provided. 1. Introduction There are several forms of Transmissible Spongiform Encephalopathy (TSE) diseases or prion diseases affecting humans and different species of farm and wild animals (i.e., sheep, cattle, and cervids). Some of them have an apparently spontaneous occurrence (i.e., sporadic and genetic TSEs; some forms of atypical bovine spongiform encephalopathy or scrapie), while others are linked to the consumption of prion-contaminated food as in the variant Creutzfeldt-Jakob disease (CJD) [1], feedstuff in bovine spongiform encephalopathy (BSE) [2], or medical and surgical devices in iatrogenic CJD [3]. Transmission of variant CJD via blood transfusion and possibly plasma-derived factor VIII from asymptomatic donors [4] indicates that prion infectivity is present in blood months or years before clinical onset. Thus, the occurrence of epidemics in farm animals and episodes of human cases linked to prion infection pose serious public health issues that are often difficult to solve [5]. An eloquent example is given by the yet unexplained discrepancy between mortality (176 death from 1995 to June 2013) [6] and estimated prevalence data (1 in 4,000 to 1 in 10,000 people) of variant CJD in the British population [7]. This incongruity is causing great concerns because healthy and