Preventive or promotive effects of PRNP polymorphic heterozygosity on the onset of prion disease

Hideaki Kai; Kenta Teruya; Atsuko Takeuchi; Yoshikazu Nakamura; Hidehiro Mizusawa; Masahito Yamada; Tetsuyuki Kitamoto

doi:10.1016/j.heliyon.2023.e13974

Preventive or promotive effects of PRNP polymorphic heterozygosity on the onset of prion disease

Heliyon. 2023 Feb 24;9(3):e13974. doi: 10.1016/j.heliyon.2023.e13974. eCollection 2023 Mar.

Authors

Hideaki Kai¹, Kenta Teruya², Atsuko Takeuchi¹, Yoshikazu Nakamura³, Hidehiro Mizusawa⁴, Masahito Yamada⁵, Tetsuyuki Kitamoto¹

Affiliations

¹ Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
² Department of Neurochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
³ Division of Public Health, Center for Community Medicine, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
⁴ Department of Neurology, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-0031, Japan.
⁵ Division of Neurology, Department of Internal Medicine, Kudanzaka Hospital, Chiyoda-ku, Tokyo 102-0074, Japan.

Abstract

The polymorphic heterozygosity of PRNP at codon 129 or 219 prevents the onset of sporadic Creutzfeldt-Jakob disease (sCJD). We investigated the association between polymorphic genotypes at codon 129 or 219 and comprehensive prion disease onset using non-CJD as a reference. EK heterozygotes at codon 219, versus EE homozygotes, showed a preventive effect on the extensive prion diseases-sCJD, genetic CJD (gCJD) with V180I or M232R mutation, and Gerstmann-Straussler-Scheinker disease with P102L mutation. No preventive effect was observed for E200K-gCJD and dura-grafted CJD (dCJD) in 129 MV and 219 EK heterozygotes. It was suggested that unlike other prion diseases, E200K-gCJD may not benefit from the preventive effect of 219 EK heterozygosity because complementary electrostatic interactions between PrP molecules at K200 and E219 might make homodimer formation easier. Comparison of sCJD and dCJD indicates that 219 EK heterozygosity strongly inhibits de novo synthesis of PrP^Sc (initial PrP^Sc formation), but does not inhibit accelerated propagation of existing PrP^Sc.

Keywords: CJD, Creutzfeldt-Jakob disease; Codon 129; Codon 219; Creutzfeldt-jakob disease; Dimer; E, glutamate; Electrostatic interaction; GSS, Gerstmann-Straussler-Scheinker disease; Genetic prion disease; Heterozygosity; K, lysine; M, methionine; OR, odds ratio; PRNP; Polymorphism; PrP, prion protein; Prion; V, valine.