Subtyping of human cellular prion proteins and their differential solubility

A human form of a prion disorder is the Creutzfeldt-Jakob disease. A hallmark of the disease is the accumulation of misfolded prion proteins (PrPSc), which exist as heterogeneous subtypes. PrPSc is formed by protein conversion from the host-encoded cellular prion (PrPC), which is expressed and modified to various isoforms. Little is known about variation in PrPC; however, it is assumed that PrPC types play important roles in the formation of PrPSc. In this study, we separated distinct human PrPC subtypes on the basis of differential protein solubilities in detergent solutions. Single and sequential application of the detergents Triton X-100, octyl-glucopyranoside and CHAPS facilitated high solubility of glycosylated PrPC isoforms, whereas high proportions of nonglycosylated PrPC remained non-soluble. Most proteins became highly soluble with laurylsarcosine and sodium dodecyl sulphate. Our findings demonstrate that the solubility characteristics of heterogeneous PrPC overlap in human brains and convey distinct solubility subtypes. Differentiation by solubility experiments can therefore provide valuable information on prion protein composition, facilitate the separation of subtypes, and offer new prospects for conversion specificity of distinct isoforms.