Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible through iatrogenic routes due to abundant infectious prions [misfolded forms of the prion protein (PrPSc)] in the central nervous system (CNS). Some epidemiological studies have associated sCJD risk with non-CNS surgeries. We explored the potential prion seeding activity and infectivity of skin from sCJD patients. Autopsy or biopsy skin samples from 38 patients [21 sCJD, 2 variant CJD (vCJD), and 15 non-CJD] were analyzed by Western blotting and real-time quaking-induced conversion (RT-QuIC) for PrPSc. Skin samples from two patients were further examined for prion infectivity by bioassay using two lines of humanized transgenic mice. Western blotting revealed dermal PrPSc in one of five deceased sCJD patients and one of two vCJD patients. However, the more sensitive RT-QuIC assay detected prion seeding activity in skin from all 23 CJD decedents but not in skin from any non-CJD control individuals (with other neurological conditions or other diseases) during blinded testing. Although sCJD patient skin contained ~103- to 105-fold lower prion seeding activity than did sCJD patient brain tissue, all 12 mice from two transgenic mouse lines inoculated with sCJD skin homogenates from two sCJD patients succumbed to prion disease within 564 days after inoculation. Our study demonstrates that the skin of sCJD patients contains both prion seeding activity and infectivity, which raises concerns about the potential for iatrogenic sCJD transmission via skin.
The four glycoforms of the cellular prion protein (PrPC) variably glycosylated at the two N-linked glycosylation sites are converted into their pathological forms (PrPSc) in most cases of sporadic prion diseases. However, a prominent molecular characteristic of PrPSc in the recently identified variably protease-sensitive prionopathy (VPSPr) is the absence of a diglycosylated form, also notable in familial Creutzfeldt-Jakob disease (fCJD), which is linked to mutations in PrP either from Val to Ile at residue 180 (fCJDV180I) or from Thr to Ala at residue 183 (fCJDT183A). Here we report that fCJDV180I, but not fCJDT183A, exhibits a proteinase K (PK)-resistant PrP (PrPres) that is markedly similar to that observed in VPSPr, which exhibits a five-step ladder-like electrophoretic profile, a molecular hallmark of VPSPr. Remarkably, the absence of the diglycosylated PrPres species in both fCJDV180I and VPSPr is likewise attributable to the absence of PrPres glycosylated at the first N-linked glycosylation site at residue 181, as in fCJDT183A. In contrast to fCJDT183A, both VPSPr and fCJDV180I exhibit glycosylation at residue 181 on di- and monoglycosylated (mono181) PrP prior to PK-treatment. Furthermore, PrPV180I with a typical glycoform profile from cultured cells generates detectable PrPres that also contains the diglycosylated PrP in addition to mono- and unglycosylated forms upon PK-treatment. Taken together, our current in vivo and in vitro studies indicate that sporadic VPSPr and familial CJDV180I share a unique glycoform-selective prion formation pathway in which the conversion of diglycosylated and mono181 PrPC to PrPSc is inhibited, probably by a dominant-negative effect, or by other co-factors.
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