Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata

Kanzawa, Noriyuki; Shimozawa, Nobuyuki; Wanders, Ronald J. A.; Ikeda, Kazutaka; Murakami, Yoshiko; Waterham, Hans R.; Mukai, Satoru; Fujita, Morihisa; Maeda, Yusuke; Taguchi, Ryo; Fujiki, Yukio; Kinoshita, Taroh

doi:10.1194/jlr.m021204

Cited by 23 publications

(15 citation statements)

References 59 publications

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“…In ether lipid‐deficient CHO cells and human fibroblasts, the alkylacylglycerol moiety is replaced by a diacyl lipid. Remarkably, in these cells, the surface levels of the GPI‐anchored protein urokinase‐type plasminogen activator receptor were even drastically increased in comparison with control cells . However, a functional evaluation of the shift from alkylacyl to diacyl moiety is still missing.…”

Section: Molecular Basis and Potential Mechanisms Underlying The Phenmentioning

confidence: 91%

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

2017

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The emerging diverse roles of ether (phospho)lipids in nervous system development and function in health and disease are currently attracting growing interest. Plasmalogens, a subgroup of ether lipids, are important membrane components involved in vesicle fusion and membrane raft composition. They store polyunsaturated fatty acids and may serve as antioxidants. Ether lipid metabolites act as precursors for the formation of glycosyl-phosphatidyl-inositol anchors; others, like platelet-activating factor, are implicated in signaling functions. Consolidating the available information, we attempt to provide molecular explanations for the dramatic neurological phenotype in ether lipid-deficient human patients and mice by linking individual functional properties of ether lipids with pathological features. Furthermore, recent publications have identified altered ether lipid levels in the context of many acquired neurological disorders including Alzheimer's disease (AD) and autism. Finally, current efforts to restore ether lipids in peroxisomal disorders as well as AD are critically reviewed.

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Section: Molecular Basis and Potential Mechanisms Underlying The Phenmentioning

confidence: 91%

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

2017

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“…Fibroblasts from patients with RCDP types 1-3 and Zellweger syndrome are defective in generation of plasmalogens due to defective synthesis of 1-alkyl glycerone phosphate in the peroxisome. In addition, those fi broblasts are defective in generation of the 1-alkyl-2-acyl form of GPI and express only the diacyl form of GPI-APs ( Table 1 ) ( 27 ). It is possible that a lack of 1-alkyl-2-acyl GPI is causally related to some of these symptoms.…”

Section: Deacylation Of Inositol From Nascent Gpi-apsmentioning

confidence: 99%

“…The latter characteristic fatty chain composition of GPI, i.e., both sn 1-and sn 2-linked fatty chains are saturated in a vast majority of GPI-APs, is critically related to two unique properties of GPI-APs, i.e., association with membrane microdomains and transient homodimerization ( 25,26 ). These two characteristic lipid structures in GPI are results of two lipid remodeling reactions ( 25,27 ) (see below).…”

Section: Structural Characteristics Of Mammalian Gpi and Gpi-apmentioning

confidence: 99%

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

Kinoshita

Fujita

2016

Journal of Lipid Research

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225

165

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“…The genetic interaction seen between EL and SL metabolism in the screening, and the bidirectional co-regulation found in our lipidomics data between ceramide and ether PC, indicated that even though these lipids are very different in terms of their chemical structure, they might share functions in cell membranes so that cells could adapt to the lack of one of them by upregulating the other class. Indeed, one common function, apparent from different kingdoms of life, is as part of the lipid anchor in GPI-AP; in yeast the plasma membrane GPI-AP have a ceramide-based anchor 40 while in mammalian cells most have an ether lipid-based anchor 41 . Therefore, we speculated that SL and EL could share functions in the secretory pathway and that their selection for this function could be based on their physico-chemical properties and behavior in membranes…”

Section: Resultsmentioning

confidence: 99%

Conserved function of ether lipids and sphingolipids in the early secretory pathway

Jiménez

Leonetti

Zoni

et al. 2019

Preprint

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Sphingolipids have been shown to play important roles in physiology and cell biology, but a systematic examination of their functions is lacking. We performed a genome-wide CRISPRi screen in sphingolipid-depleted cells and identified hypersensitive mutants in genes of membrane trafficking and lipid biosynthesis, including ether lipid synthesis. Systematic lipidomic analysis showed a coordinate regulation of ether lipids with sphingolipids, where depletion of one of these lipid types resulted in increases in the other, suggesting an adaptation and functional compensation. Biophysical experiments on model membranes show common properties of these structurally diverse lipids that also share a known function as GPI anchors in different kingdoms of life. Molecular dynamics simulations show a selective enrichment of ether phosphatidylcholine around p24 proteins, which are receptors for the export of GPI-anchored proteins and have been shown to bind a specific sphingomyelin species. Our results support a model of convergent evolution of proteins and lipids, based on their physico-chemical properties, to regulate GPI-anchored protein transport and maintain homeostasis in the early secretory pathway.

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Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata

Cited by 23 publications

References 59 publications

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

From peroxisomal disorders to common neurodegenerative diseases – the role of ether phospholipids in the nervous system

Thematic Review Series: Glycosylphosphatidylinositol (GPI) Anchors: Biochemistry and Cell Biology Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling

Conserved function of ether lipids and sphingolipids in the early secretory pathway

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