PrPC is a glycosylphosphatidylinositol (GPI) anchored glycoprotein of unknown function. Misfolding of normal cellular PrPC to the pathogenic PrPSc is the hallmark of prion diseases (transmissible spongiform encephalopathies). Prion diseases are characterized by extensive neurodegeneration and early death. Understanding how PrPC maintains its correct conformation is a major endeavor of current inquiry. Here we demonstrate a novel interaction between PrPC and the J protein family member, Rdj2 (DjA2; Dj3, Dnj3, Cpr3, and Hirip4). The importance of the J protein family in the cellular folding machinery has been recognized for many years. The PrPC/Rdj2 association was direct and concentration-dependent. Other J proteins such as CSP alpha and auxilin did not associate with PrPC in the absence of ATP, demonstrating the specificity of the PrPC/J protein interaction. These findings suggest that the J protein family serves as a 'folding catalyst' for PrPC and implicates Rdj2 as a factor in the protection against prion diseases. (c) 2006 Elsevier Inc. All rights reserved.