Loss of the N-acetylgalactosamine side chain of the GPI-anchor impairs bone formation and brain functions and accelerates the prion disease pathology

Glycosylphosphatidylinositol (GPI) is a posttranslational glycolipid modification of proteins that anchors proteins in lipid rafts on the cell surface. Although some GPI-anchored proteins (GPI-APs), including the prion protein PrPC, have a glycan side chain composed of N-acetylgalactosamine (GalNAc)...

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Published in:	The Journal of biological chemistry 2022-03, Vol.298 (3), p.101720-101720, Article 101720
Main Authors:	Hirata, Tetsuya, Kobayashi, Atsushi, Furuse, Tamio, Yamada, Ikuko, Tamura, Masaru, Tomita, Hiroyuki, Tokoro, Yuko, Ninomiya, Akinori, Fujihara, Yoshitaka, Ikawa, Masahito, Maeda, Yusuke, Murakami, Yoshiko, Kizuka, Yasuhiko, Kinoshita, Taroh
Format:	Article
Language:	eng
Subjects:	Acetylgalactosamine - chemistry Acetylgalactosamine - metabolism Animals bone formation Brain - metabolism brain function Creutzfeldt–Jakob disease glycosylation Glycosylphosphatidylinositols - chemistry Glycosylphosphatidylinositols - metabolism glycosyltransferase GPI Mice Osteogenesis prion Prion Diseases - metabolism Prions - metabolism Structure-Activity Relationship
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Summary:	Glycosylphosphatidylinositol (GPI) is a posttranslational glycolipid modification of proteins that anchors proteins in lipid rafts on the cell surface. Although some GPI-anchored proteins (GPI-APs), including the prion protein PrPC, have a glycan side chain composed of N-acetylgalactosamine (GalNAc)−galactose−sialic acid on the core structure of GPI glycolipid, in vivo functions of this GPI-GalNAc side chain are largely unresolved. Here, we investigated the physiological and pathological roles of the GPI-GalNAc side chain in vivo by knocking out its initiation enzyme, PGAP4, in mice. We show that Pgap4 mRNA is highly expressed in the brain, particularly in neurons, and mass spectrometry analysis confirmed the loss of the GalNAc side chain in PrPC GPI in PGAP4-KO mouse brains. Furthermore, PGAP4-KO mice exhibited various phenotypes, including an elevated blood alkaline phosphatase level, impaired bone formation, decreased locomotor activity, and impaired memory, despite normal expression levels and lipid raft association of various GPI-APs. Thus, we conclude that the GPI-GalNAc side chain is required for in vivo functions of GPI-APs in mammals, especially in bone and the brain. Moreover, PGAP4-KO mice were more vulnerable to prion diseases and died earlier after intracerebral inoculation of the pathogenic prion strains than wildtype mice, highlighting the protective roles of the GalNAc side chain against prion diseases.
ISSN:	0021-9258 1083-351X