Affiliations: [a] Department of Physiology and Biophysics, Howard University College of Medicine, Washington, 20059 DC, USA | [b] Department of Pathology, Case Western Reserve University, Cleveland, 44106 OH, USA | [c] Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA | [d] Department of Neuroscience, Case Western Reserve University, Cleveland, 44106 OH, USA
Correspondence:
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Corresponding author: Robert B. Petersen, Case Western Reserve University, Institute of Pathology, 2085 Adelbert Road, Cleveland, 44106-2622 OH, USA. E-mail: [email protected].
Note: [**] These authors contributed equally to this work.
Abstract: Prion diseases are associated with the accumulation of a misfolded, protease resistant form of the prion protein, PrPres. In humans there are a variety of different prion related diseases that are sporadic, inherited, or acquired by infection. Gerstmann-Straussler-Sheinker syndrome (GSS) is an inherited prion disease in which PrPres accumulates as amorphous aggregates as well as in amyloid plaques. GSS has been associated with a variety of point mutations in the prion protein: 102, 105, 117, 131, 145, 187, 198, 202, 212, 217, and 232. The F198S mutation was discovered in a large Indiana kindred. Previous studies in vitro have shown that the 198 mutation results in structural instability of the prion protein. In the current study, we demonstrate in a cell model that the F198S mutant protein can be folded properly in a cellular context, but is unable to refold to a native state after denaturation. Further, the F198S mutation significantly affects glycosylation of the mutant protein.
