TY - JOUR
T1 - Co-existence of PrPD types 1 and 2 in sporadic Creutzfeldt-Jakob disease of the VV subgroup
T2 - phenotypic and prion protein characteristics
AU - Cali, Ignazio
AU - Puoti, Gianfranco
AU - Smucny, Jason
AU - Curtiss, Paul Michael
AU - Cracco, Laura
AU - Kitamoto, Tetsuyuki
AU - Occhipinti, Rossana
AU - Cohen, Mark Lloyd
AU - Appleby, Brian Stephen
AU - Gambetti, Pierluigi
N1 - Funding Information:
We thank the patients’ families, referring clinicians, the CJD Foundation and all the members of the NPDPSC, in particular we gratefully acknowledge Mses. Diane Kofskey, Miriam Warren, Yvonne Cohen and Wei Chen for their invaluable technical help, Katie Glisic and Janis Blevins for their assistance and advices. Dr. Alberto Bizzi gave advice on role of MRI in the diagnosis of sCJD type mixed cases. This study was supported by National Institutes of Health Grants R01 NS083687 and P01 AI106705, and The Charles S. Britton Fund to P. Gambetti. As a trainee of the research education component (REC) of the Cleveland Alzheimer’s Disease Research Center (CADRC), the work of I. Cali was in part supported by the National Institute of Aging P30 AG062428 01 grant. The work of RO was in part supported by NIH grant K01 DK107787.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - We report a detailed study of a cohort of sporadic Creutzfeldt-Jakob disease (sCJD) VV1–2 type-mixed cases (valine homozygosity at codon 129 of the prion protein, PrP, gene harboring disease-related PrP, PrPD, types 1 and 2). Overall, sCJDVV1–2 subjects showed mixed clinical and histopathological features, which often correlated with the relative amounts of the corresponding PrPD type. However, type-specific phenotypic characteristics were only detected when the amount of the corresponding PrPD type exceeded 20–25%. Overall, original features of types 1 (T1) and 2 (T2) in sCJDVV1 and -VV2, including rostrocaudal relative distribution and conformational indicators, were maintained in sCJDVV1–2 except for one of the two components of T1 identified by electrophoretic mobility as T121. The T121 conformational characteristics shifted in the presence of T2, inferring a conformational effect of PrPD T2 on T121. The prevalence of sCJDVV1–2 was 23% or 57% of all sCJDVV cases, depending on whether standard or highly sensitive type-detecting procedures were adopted. This study, together with previous data from sCJDMM1–2 (methionine homozygosity at PrP gene codon 129) establishes the type-mixed sCJD variants as an important component of sCJD, which cannot be identified with current non-tissue based diagnostic tests of prion disease.
AB - We report a detailed study of a cohort of sporadic Creutzfeldt-Jakob disease (sCJD) VV1–2 type-mixed cases (valine homozygosity at codon 129 of the prion protein, PrP, gene harboring disease-related PrP, PrPD, types 1 and 2). Overall, sCJDVV1–2 subjects showed mixed clinical and histopathological features, which often correlated with the relative amounts of the corresponding PrPD type. However, type-specific phenotypic characteristics were only detected when the amount of the corresponding PrPD type exceeded 20–25%. Overall, original features of types 1 (T1) and 2 (T2) in sCJDVV1 and -VV2, including rostrocaudal relative distribution and conformational indicators, were maintained in sCJDVV1–2 except for one of the two components of T1 identified by electrophoretic mobility as T121. The T121 conformational characteristics shifted in the presence of T2, inferring a conformational effect of PrPD T2 on T121. The prevalence of sCJDVV1–2 was 23% or 57% of all sCJDVV cases, depending on whether standard or highly sensitive type-detecting procedures were adopted. This study, together with previous data from sCJDMM1–2 (methionine homozygosity at PrP gene codon 129) establishes the type-mixed sCJD variants as an important component of sCJD, which cannot be identified with current non-tissue based diagnostic tests of prion disease.
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U2 - 10.1038/s41598-020-58446-0
DO - 10.1038/s41598-020-58446-0
M3 - Article
C2 - 32001774
AN - SCOPUS:85078713101
VL - 10
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 1503
ER -