Mechanisms of phenotypic heterogeneity in prion, Alzheimer and other conformational diseases

Department of Physiology, East Carolina University,Greenville, NC 27858, USA1. IntroductionOneof thechallengesfacedbyclinicians andpathol-ogistsis dealingwiththevariabilityoftheclinicalsignsandofthepathologicalchangesthatareassociatedwithdiseases. The truism that two patients with the samedisease are never identical poses no serious diagnosticproblems under most circumstances. However, therearediseasesthatpresentconsiderablevariabilityintheirclinical and pathological phenotype, which not onlymakes the diagnosis difficult but also raises the issue ofthe mechanisms that regulate it.While phenotypically Alzheimer disease, amy-otrophic lateral sclerosis and Huntington chorea havebeenconsideredfairlyhomogenousdiseases, priondis-eases include several clinically and pathologically dis-tinct conditions (Table 1) [33]. Until a few years ago,the sporadic form of prion diseases included only theCreutzfeldt-Jakobdisease(CJD)phenotype. Theinher-ited form included familial CJD, fatal familial insom-nia (FFI), and Gerstmann-Straussler-Scheinkerdisease¨(GSS). These three phenotypes are quite different andhave very unique features. In addition, a fourth sub-typeoffamilialpriondiseases associatedwithinsertionmutationshas eithera mixedphenotypewhichincludesfeatures of both CJD and GSS or a pathological phe-notype with no distinctive features. The form acquiredby infection consists of three phenotypes that are alsoquite distinct, namely the iatrogenic CJD, kuru, andthe new variant CJD reported almost exclusively in theUnited Kingdom.A major interest of our group has been the studyof the mechanisms that regulate the phenotypic het-erogeneity. The understanding of these mechanismsmay lead to a classification of prion diseases based onthe causes rather than the effects of this heterogene-ity. Such classification is likely to be more accurateand may result in a wider detection and more precisediagnosis of these diseases.2. Molecular, cell biology and pathology of theprion proteinThematurenormalorcellularprionprotein(PrP