Regional phenotypes of cellular prion proteins in human brains identified by differential detergent solubility.

A hallmark of prion diseases is the accumulation of disease-associated isoforms (PrP(Sc)) which results from the conversion of host-encoded cellular prion proteins (PrP(C)). Using molecular biochemistry, several disease variants of the human Creutzfeldt-Jakob disease have been identified showing several PrP(Sc) variants in individuals and selective accumulation in specific brain regions. As PrP(C) is differentially expressed and post-translationally modified, certain distinct protein compositions may have the ability to convert more efficiently than others. The PrP(C) glycoprotein moiety represents a single yet divers mixture, but little is known about its exact composition. In this study, we separated and characterized PrP(C) derived from six defined human brain regions in regard to their solubility in several detergent solutions and glycoprotein profile formation. We identified four different but regionally distinct protein compositions. PrP(C) found in the neocortex exhibited dominant diglycosylated bands in the high as well as in the low soluble fractions. The proteins in the nucleus lentiformis, thalamus and hippocampus were more soluble with deoxycholic acid as the N-octyl-β-d-glucopyranoside and the diglycosylated bands displayed strong signals in the supernatants and weaker signals in the sediments. Two different protein profiles were established with PrP(C) derived from the medulla oblongata and the solubility of PrP(C) in the cerebellum clearly differed by the choice of detergent. Our findings indicate the existence of several distinct PrP(C) compositions localized in distinct brain regions. Protein variations may be induced by specific modifications to specific regional biological functions.