[Source: American Journal of Pathology, full page: (LINK). Abstract, edited.]
Ganglioside synthase knock-out reduces prion disease incubation time in mouse models
Atsushi Kobayashi, , Zechen Qi, Taishi Shimazaki, Yoshiko Munesue, Tomomi Miyamoto, Norikazu Isoda, Hirofumi Sawa, Keisuke Aoshima, Takashi Kimura, Shirou Mohri, Tetsuyuki Kitamoto, Tadashi Yamashita, Ichiro Miyoshi
Accepted: November 16, 2018 – Received in revised form: November 14, 2018 – Received: September 4, 2018
Localization of the abnormal and normal isoforms of prion proteins to detergent-resistant membrane microdomains, lipid rafts, is important for the conformational conversion. Lipid rafts are enriched in sialic acid–containing glycosphingolipids, namely gangliosides. Alteration in the ganglioside composition of lipid rafts can affect the localization of lipid raft–associated proteins. To investigate the role of gangliosides in the pathogenesis of prion diseases, we performed intracerebral transmission study of a scrapie prion strain Chandler and a Gerstmann-Sträussler-Scheinker syndrome prion strain Fukuoka-1 using various knock-out mouse strains ablated with ganglioside synthase gene, ie, GD2/GM2 synthase, GD3 synthase, or GM3 synthase. Following challenge with the Chandler strain, GD2/GM2 synthase knock-out mice showed 20% reduction of incubation time, reduced prion protein deposition in the brain with attenuated glial reactions, and reduced localization of prion proteins to lipid rafts. These results raise the possibility that the gangliosides may have an important role in prion disease pathogenesis by affecting the localization of prion proteins to lipid rafts.
Funding: Supported by Grants-in-Aid for Scientific Research from JSPS (18K05963; A.K.), The Ichiro Kanehara Foundation (A.K.), The Suhara Memorial Foundation (A.K.), and The Kato Memorial Trust for Nambyo Research (A.K.).
Disclosures: None declared.
© 2018 Published by Elsevier Inc. on behalf of the American Society for Investigative Pathology.
Keywords: Prions; Scrapie; Gangliosides; Animal models.