Distinctive properties of the prion protein in the brain and retina in the amyloidosis associated with the PRNP F198S mutation

Prion protein (PrP) deposits in the form of diffuse and cored plaques occur in most gray matter areas of the brain of individuals affected by Gerstmann-Str & auml;ussler-Scheinker disease (GSS) associated with the F198S mutation in PRNP; however, the PrP deposits in the retina have not been characterized. Furthermore, a comparative analysis of PrP deposits occurring in the brain and in the retina in GSS has not been carried out. We hypothesize that the PrP aggregation and seeding properties in the brain and retina differ. The aim of this study was to analyze PrP from brains and retinas of individuals affected by GSS, all carriers of the PRNP F198S mutation from the same pedigree. Postmortem tissues from these patients were analyzed using neuropathologic and biochemical methods including Real-Time Quaking Induced Conversion assay. PrP deposits in the retina were found only in the outer plexiform layer, did not have tinctorial property of amyloid and were immunopositive using nine antibodies recognizing epitopes throughout the PrP sequence. Biochemical analysis showed that PrP_F198S in the retina is partially detergent-insoluble, is assembled in large-size aggregates, and has seeding property. In addition, the glycosylation of full-length PrP in the retina was more complex than that of control PrP. Furthermore, the homogenates of retina did not contain the 8 kDa PrP internal fragments (PrPIF) as brain homogenates do; however, a PrPIF was experimentally generated using proteinase K. In conclusion, we report for the first time the neuropathologic and biochemical properties of PrP in the retina of individuals carrying PRNP F198S and compare them with those in the brain of the same individuals. The fact that in GSS F198S, PrPIF is constitutive only in the brain points to the need of identifying whether there is a difference in proteolytic mechanisms between retina and brain.