Recent advances in the biochemistry and genetics of sphingolipidoses

Özkara, Hatice Asuman

doi:10.1016/j.braindev.2004.01.005

Cited by 27 publications

(17 citation statements)

References 65 publications

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“…in alkenyl‐acyl species of phosphatidylethanolamines and in glycosphingolipids with 20‐ and 24‐carbon acyl chains (Rao 1977; Martinez 1982). Moreover, altered concentrations of plasmalogens and glycosphingolipids have been reported in several neurological diseases, such as Alzheimer’s disease, adrenoleukodystrophy, and sphingolipidoses (Ozkara 2004; Hartmann et al. 2007; Khan et al.…”

Section: Discussionmentioning

confidence: 99%

Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain

Mutka

Haapanen

Käkelä

et al. 2009

Journal of Neurochemistry

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1Both these authors contributed equally to this study.Abbreviations used: ABCA1, ATP-binding casette transporter A1; ApoE, apolipoprotein E; CNP, 2¢,3¢-cyclic nucleotide 3¢-phosphodiesterase; CTSD, cathepsin D; EM, electron microscopy; IPG, immobilized pH gradient; iTRAQ, isobaric tags for absolute and relative quantitation; LFB, Luxol fast blue; MBP, myelin basic protein; MS, mass spectrometry; P24, postnatal day 24; PC, principal component; PE, phosphatidylethanolamine; PLP, proteolipid protein; SAP, sphingolipid activator protein. AbstractCathepsin D (CTSD) deficiencies are fatal neurological diseases that in human infants and in sheep are characterized by extreme loss of neurons and myelin. To date, similar morphological evidence for myelin disruption in CTSD knockout mice has not been reported. Here, we show that CTSD deficiency leads to pronounced myelin changes in the murine brain: myelin-related proteolipid protein and myelin basic protein were both markedly reduced at postnatal day 24, and the amount of lipids characteristically high in myelin (e.g. plasmalogen-derived alkenyl chains and glycosphingolipidderived 20-and 24-carbon acyl chains) were significantly lowered compared with controls. These changes were accompanied by ultrastructural alterations of myelin, including significant thinning of myelin sheaths. Furthermore, in CTSD knockout brains there was a pronounced accumulation of cholesteryl esters and abnormal levels of proteins related to cholesterol transport, with an increased content of apolipoprotein E and a reduced content of ATP-binding cassette transporter A1. These results provide evidence for dysmyelination and altered trafficking of cholesterol in brains of CTSD knockout mice, and warrant further studies on the role of lipid metabolism in the pathogenesis of CTSD deficiencies.

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Section: Discussionmentioning

confidence: 99%

Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain

Mutka

Haapanen

Käkelä

et al. 2009

Journal of Neurochemistry

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“…Whereas mucopolysaccharidoses are inherited deficiencies of enzymes involved in glycosaminoglycan breakdown (Coutinho et al, 2012), sphingolipidoses are caused by malfunction of enzymes that are involved in the breakdown of sphingolipids (Ozkara, 2004;Eckhardt, 2010). Gaucher disease is the most common sphingolipidosis.…”

Section: Lysosomal Storage Disordersmentioning

confidence: 99%

Role of TRPML and Two-Pore Channels in Endolysosomal Cation Homeostasis

Grimm¹,

Hassan²,

Wahl‐Schott³

et al. 2012

J Pharmacol Exp Ther

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The transient receptor potential (TRP) channels TRPML1, TRPML2, and TRPML3 (also called mucolipins 1-3 or MCOLN1-3) are nonselective cation channels. Mutations in the Trpml1 gene cause mucolipidosis type IV in humans with clinical features including psychomotor retardation, corneal clouding, and retinal degeneration, whereas mutations in the Trpml3 gene cause deafness, circling behavior, and coat color dilution in mice. No disease-causing mutations are reported for the Trpml2 gene. Like TRPML channels, which are expressed in the endolysosomal pathway, two-pore channels (TPCs), namely TPC1, TPC2, and TPC3, are found in intracellular organelles, in particular in endosomes and lysosomes. Both TRPML channels and TPCs may function as calcium/cation release channels in endosomes, lysosomes, and lysosome-related organelles with TRPMLs being activated by phosphatidylinositol 3,5-bisphosphate and regulated by pH and TPCs being activated by nicotinic acid adenine dinucleotide phosphate in a calcium-and pH-dependent manner. They may also be involved in endolysosomal transport and fusion processes, e.g., as intracellular calcium sources. Currently, however, the exact physiological roles of TRPML channels and TPCs remain quite elusive, and whether TRPML channels are purely endolysosomal ion channels or whether they may also be functionally active at the plasma membrane in vivo remains to be determined.

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“…Sphingolipidoses 4 were helpful in investigating glycosphingolipid digestion. The catabolic enzymes and mechanisms were described by characterisation of these diseases [19]. Degradation of the glycosphingolipids takes place in the acidic compartments (lysosomes and endosomes) of the cell.…”

Section: Digestion Of Glycosphingolipidsmentioning

confidence: 99%

Occurrence and Biological Properties of Sphingolipids - A Review

Wehrmüller

2007

CNF

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Sphingolipids are a complex group of polar lipids. Variations in their components (backbone, polar head group and fatty acid) engenders a large and complex structural variety which affects the biological properties of the individual molecules. Sphingolipids are omnipresent in foodstuffs, can cross the intestinal barrier and are biologically active. The quantities in food range from a few g/kg in fruits and some vegetables up to 1 g/kg in milk products, eggs, meat and soybeans. Several positive impacts of sphingolipids on human health have been described: In vitro experiments measuring the antibacterial properties of sphingolipids have been successfully carried out. A sphingolipid-enriched diet showed inhibitory effects on the formation of early colon carcinoma precursors (Aberrant Crypt Foci (ACF)) in mice. Sphingolipid metabolites also induce apoptosis in transformed human cell cultures. Taken together, there is a high probability that sphingolipids have anticancerogenic properties in humans. Finally, a specific group of sphingolipids is essential for the maintenance of nerve function and structure and the enrichment of sphingomyelin in a cholesterol-rich diet successfully reduces cholesterol absorption. Although sphingolipids are probably not essential dietary components, they can significantly contribute to human health.This article reviews the present state of knowledge concerning the occurrence and biological properties of sphingolipids.

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Recent advances in the biochemistry and genetics of sphingolipidoses

Cited by 27 publications

References 65 publications

Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain

Murine cathepsin D deficiency is associated with dysmyelination/myelin disruption and accumulation of cholesteryl esters in the brain

Role of TRPML and Two-Pore Channels in Endolysosomal Cation Homeostasis

Occurrence and Biological Properties of Sphingolipids - A Review

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