Conformational conversion of the cellular isoform of prion protein, designated PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, plays a key pathogenic role in prion diseases, including Creutzfeldt-Jacob disease in humans. We previously reported that sortilin, a member of the vacuolar protein sorting 10 protein (VPS10P) domain receptor family, could play a protective role in prion disease by functioning as a cargo receptor that delivers PrPC and PrPSc to lysosomes for degradation. In this study, we generated transgenic mice overexpressing sortilin, termed TgSortilin mice, and intracerebrally inoculated them and control mice with various mouse-adapted prion strains.
TgSortilin mice exhibited lower PrPC levels in their brains, although PrP mRNA levels were comparable between TgSortilin and control mice, suggesting that sortilin overexpression reduces PrPC levels, probably through lysosomal degradation of PrPC. Consistent with this, TgSortilin mice showed reduced susceptibility to prion infection. They eventually developed prion disease after inoculation, but with prolonged incubation times and lower brain accumulation of PrPSc, to varying degrees depending on the inoculated prion strains.
These findings indicate that sortilin overexpression lowers PrPC levels and thereby delays prion pathogenesis, suggesting that sortilin-mediated PrPC degradation may be a potential therapeutic target in prion diseases. BB gratefully acknowledges financial support from the Japanese Government (MEXT, No. 233034) Scholarship Program. This work was supported in part by JSPS KAKENHI 23H02798 and 23K27489 to SS.
Batzaya Batchuluun and Hironori Miyata contributed equally to this work. Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima, 770-8503, Japan Batzaya Batchuluun, Nandita Rani Das, Khurelbaatar Bolorchimeg, Junji Chida & Suehiro Sakaguchi Animal Research Center, School of Medicine, University of Occupational and Environmental Health, 1-1 Yahatanishi, Kitakyushu, 807-8555, Japan The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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