Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models
2010; Elsevier BV; Volume: 52; Issue: 3 Linguagem: Inglês
10.1194/jlr.r009761
ISSN1539-7262
AutoresRoman Chrast, Gesine Saher, Klaus-Armin Nave, Mark H. G. Verheijen,
Tópico(s)Metabolism and Genetic Disorders
ResumoThe integrity of central and peripheral nervous system myelin is affected in numerous lipid metabolism disorders. This vulnerability was so far mostly attributed to the extraordinarily high level of lipid synthesis that is required for the formation of myelin, and to the relative autonomy in lipid synthesis of myelinating glial cells because of blood barriers shielding the nervous system from circulating lipids. Recent insights from analysis of inherited lipid disorders, especially those with prevailing lipid depletion and from mouse models with glia-specific disruption of lipid metabolism, shed new light on this issue. The particular lipid composition of myelin, the transport of lipid-associated myelin proteins, and the necessity for timely assembly of the myelin sheath all contribute to the observed vulnerability of myelin to perturbed lipid metabolism. Furthermore, the uptake of external lipids may also play a role in the formation of myelin membranes. In addition to an improved understanding of basic myelin biology, these data provide a foundation for future therapeutic interventions aiming at preserving glial cell integrity in metabolic disorders. The integrity of central and peripheral nervous system myelin is affected in numerous lipid metabolism disorders. This vulnerability was so far mostly attributed to the extraordinarily high level of lipid synthesis that is required for the formation of myelin, and to the relative autonomy in lipid synthesis of myelinating glial cells because of blood barriers shielding the nervous system from circulating lipids. Recent insights from analysis of inherited lipid disorders, especially those with prevailing lipid depletion and from mouse models with glia-specific disruption of lipid metabolism, shed new light on this issue. The particular lipid composition of myelin, the transport of lipid-associated myelin proteins, and the necessity for timely assembly of the myelin sheath all contribute to the observed vulnerability of myelin to perturbed lipid metabolism. Furthermore, the uptake of external lipids may also play a role in the formation of myelin membranes. In addition to an improved understanding of basic myelin biology, these data provide a foundation for future therapeutic interventions aiming at preserving glial cell integrity in metabolic disorders. MYELIN: A GIANT MEMBRANE ORGANELLE WITH SPECIFIC LIPID CHARACTERISTICSThe rapid saltatory conduction of action potentials along axons is crucially dependent on myelination. The myelin membrane is an extended and highly specialized plasma membrane synthesized by myelinating glial cells: oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS) (Fig. 1). The wrapping of myelin around an axonal segment increases axonal resistance and enables clustering of axonal ion channels at nodes of Ranvier (1Barres B.A. The mystery and magic of glia: a perspective on their roles in health and disease.Neuron. 2008; 60: 430-440Abstract Full Text Full Text PDF PubMed Scopus (781) Google Scholar). As such, myelinating glial cells shape the structural and electrical properties of axons resulting in a 10- to 100-fold increase in nerve conduction velocity (2Franz D.N. Iggo A. Conduction failure in myelinated and non-myelinated axons at low temperatures.J. Physiol. 1968; 199: 319-345Crossref PubMed Google Scholar, 3Waxman S.G. Determinants of conduction velocity in myelinated nerve fibers.Muscle Nerve. 1980; 3: 141-150Crossref PubMed Google Scholar) and in a great reduction of axonal energy consumption (4Hartline D.K. Colman D.R. Rapid conduction and the evolution of giant axons and myelinated fibers.Curr. Biol. 2007; 17: R29-R35Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar).One of the prominent biochemical characteristics that distinguishes myelin from other membranes is its high lipid-to-protein ratio; lipids account for at least 70% of the dry weight of myelin membranes (Table 1), which is also the physical basis for its biochemical purification by sucrose gradient centrifugation (5Norton W.T. Poduslo S.E. Myelination in rat brain: method of myelin isolation.J. Neurochem. 1973; 21: 749-757Crossref PubMed Google Scholar).TABLE 1Approximate lipid composition of the myelin membraneMyelin MembraneaFrom Norton and Poduslo 1973 (6): myelin of adult rat brain. Comparable lipid amounts are present in myelin of rodent peripheral nerve, with the exception of much higher SM levels (10–35%) (7).Liver CellPlasma MembranebFrom Dod and Gray, 1968 (164): plasma membrane of adult rat liver. The category 'other lipids’ contains free fatty acids, triglycerides and cholesterol esters, which could be indicative for contamination by other membranes. Comparable lipid amounts were found by Ray et al., 1968 (165). Bold numbers indicate percentages of lipids enriched in myelin, as discussed in the text.Lipid content (dry weight)71%34%Lipid classCholesterol26%17%PhospholipidsPE16%7%PS6%4%PC12%24%PI1%4SM3%20%Glycolipids31%7%Other lipids5%17%a From Norton and Poduslo 1973 (6Norton W.T. Poduslo S.E. Myelination in rat brain: changes in myelin composition during brain maturation.J. Neurochem. 1973; 21: 759-773Crossref PubMed Google Scholar): myelin of adult rat brain. Comparable lipid amounts are present in myelin of rodent peripheral nerve, with the exception of much higher SM levels (10–35%) (7Garbay B. Heape A.M. Sargueil F. Cassagne C. Myelin synthesis in the peripheral nervous system.Prog. Neurobiol. 2000; 61: 267-304Crossref PubMed Scopus (205) Google Scholar).b From Dod and Gray, 1968 (164Dod B.J. Gray G.M. The lipid composition of rat-liver plasma membranes.Biochim. Biophys. Acta. 1968; 150: 397-404Crossref PubMed Google Scholar): plasma membrane of adult rat liver. The category 'other lipids’ contains free fatty acids, triglycerides and cholesterol esters, which could be indicative for contamination by other membranes. Comparable lipid amounts were found by Ray et al., 1968 (165Ray T.K. Skipski V.P. Barclay M. Essner E. Archibald F.M. Lipid composition of rat liver plasma membranes.J. Biol. Chem. 1969; 244: 5528-5536Abstract Full Text PDF PubMed Google Scholar). Bold numbers indicate percentages of lipids enriched in myelin, as discussed in the text. Open table in a new tab The myelin membrane contains myelin-specific proteins (e.g., myelin basic protein, myelin-associated glycoprotein, and proteolipid protein), but no truly myelin-specific lipids. Nevertheless, whereas all major lipid classes are present in myelin as in other membranes, myelin has its characteristic lipid composition. The myelin membrane contains a high level of cholesterol of at least 26% by weight (or 52 mol%) (Table 1) (6Norton W.T. Poduslo S.E. Myelination in rat brain: changes in myelin composition during brain maturation.J. Neurochem. 1973; 21: 759-773Crossref PubMed Google Scholar, 7Garbay B. Heape A.M. Sargueil F. Cassagne C. Myelin synthesis in the peripheral nervous system.Prog. Neurobiol. 2000; 61: 267-304Crossref PubMed Scopus (205) Google Scholar). The importance of cholesterol for myelin production and maintenance has recently been reviewed (8Saher G. Simons M. Cholesterol and myelin biogenesis.Subcell. Biochem. 2010; 51: 489-508Crossref PubMed Scopus (45) Google Scholar). The myelin membrane is also substantially enriched in galactolipids (31% vs. 7% for liver cell plasma membranes). Two glycosphingolipids, the monogalactosylsphingolipids cerebroside and sulfatide account for 14%–26% and 2%–7% of myelin lipids, respectively (9Norton W.T. Cammer W. Myelin P. Morell Isolation and characterization of myelin. Plenum, New York1984: 147-180Google Scholar, 10Stoffel W. Bosio A. Myelin glycolipids and their functions.Curr. Opin. Neurobiol. 1997; 7: 654-661Crossref PubMed Scopus (111) Google Scholar, 11Eckhardt M. The role and metabolism of sulfatide in the nervous system.Mol. Neurobiol. 2008; 37: 93-103Crossref PubMed Scopus (114) Google Scholar). When compared with hepatocyte and erythrocyte membranes, myelin membranes also contain a higher proportion of saturated long-chain fatty acids (Fig. 2). Finally, the lipid content of myelin is also enriched in plasmalogens (etherlipids). These glycerophospholipids, defined by a vinyl ether double bond at the sn-1 position, account for 20% of the myelin phospholipid mass (compared with 18% in the average human phospholipid mass). Here, 70% of the total phosphatidylethanolamine in white matter is plasmalogen, in contrast to only 5% in liver (12Nagan N. Zoeller R.A. Plasmalogens: biosynthesis and functions.Prog. Lipid Res. 2001; 40: 199-229Crossref PubMed Scopus (386) Google Scholar, 13Balakrishnan S. Goodwin H. Cumings J.N. The distribution of phosphorus-containing lipid compounds in the human brain.J. Neurochem. 1961; 8: 276-284Crossref PubMed Scopus (17) Google Scholar). These lipid characteristics of myelin, together with the presence of myelin-specific proteins, are likely required for myelin wrapping and/or to confer the specific biophysical properties of myelin as an electrical “insulator”, as will be discussed below.Fig. 2Fatty acid composition of myelin compared with other membranes. Depicted is the amount of fatty acid in mol percentage of total amount of fatty acids. Bold numbered and gray numbered lipids depict, respectively, strongly higher or lower levels of these fatty acids in myelin compared with hepatocytes or erythrocyte membranes. Myelin membrane of mouse sciatic nerve were isolated as described in (110Verheijen M.H. Camargo N. Verdier V. Nadra K. de Preux Charles A.S. Medard J.J. Luoma A. Crowther M. Inouye H. Shimano H. SCAP is required for timely and proper myelin membrane synthesis.Proc. Natl. Acad. Sci. USA. 2009; 106: 21383-21388Crossref PubMed Scopus (69) Google Scholar, 163Retra K. Bleijerveld O.B. van Gestel R.A. Tielens A.G. van Hellemond J.J. Brouwers J.F. A simple and universal method for the separation and identification of phospholipid molecular species.Rapid Commun. Mass Spectrom. 2008; 22: 1853-1862Crossref PubMed Scopus (77) Google Scholar). Mouse erythrocyte membranes and hepatocyte phospholipids were isolated and analyzed according to (110Verheijen M.H. Camargo N. Verdier V. Nadra K. de Preux Charles A.S. Medard J.J. Luoma A. Crowther M. Inouye H. Shimano H. SCAP is required for timely and proper myelin membrane synthesis.Proc. Natl. Acad. Sci. USA. 2009; 106: 21383-21388Crossref PubMed Scopus (69) Google Scholar, 163Retra K. Bleijerveld O.B. van Gestel R.A. Tielens A.G. van Hellemond J.J. Brouwers J.F. A simple and universal method for the separation and identification of phospholipid molecular species.Rapid Commun. Mass Spectrom. 2008; 22: 1853-1862Crossref PubMed Scopus (77) Google Scholar). It should be noted that under the isolation conditions used, amide bonds in sphingolipids are relatively stable. Hence, the very long-chain fatty acids found in myelin are not reflecting the high level of galactosphingolipids in myelin, but are more likely to result from a particular fatty acyl composition of the glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine). In addition, with the detection method used, the bar representing 18:1 fatty acids does not include 18:1 alcohol of plasmalogens, which nevertheless was previously detected to be very low in PNS myelin in mouse (110Verheijen M.H. Camargo N. Verdier V. Nadra K. de Preux Charles A.S. Medard J.J. Luoma A. Crowther M. Inouye H. Shimano H. SCAP is required for timely and proper myelin membrane synthesis.Proc. Natl. Acad. Sci. USA. 2009; 106: 21383-21388Crossref PubMed Scopus (69) Google Scholar).View Large Image Figure ViewerDownload Hi-res image Download (PPT)During development of the human nervous system, myelination starts in the motor roots of the PNS (fifth fetal month) and is followed by myelination of the spinal cord and brain (CNS). The majority of myelin is assembled during the first two years of postnatal life (14Morell P. Quarles R.H. Myelin formation, structure and biochemistry.in: George J.S. Agranoff B.W. Albers R.W. Fisher S.F. Uhler M.D. Basic Neurochemistry. Lippincott-Raven, Philedelphia1999Google Scholar), but myelination continues for 2–3 decades in the human cerebral white matter (15Sowell E.R. Peterson B.S. Thompson P.M. Welcome S.E. Henkenius A.L. Toga A.W. Mapping cortical change across the human life span.Nat. Neurosci. 2003; 6: 309-315Crossref PubMed Scopus (1576) Google Scholar, 16Yakovlev P.I. Lecours A.R. The myelogenetic cycles of regional maturation of the brain.in: Minkowski A. Regional Development of the Brain in Early Life. Blackwell Scientific, Oxford1967: 3-70Google Scholar). In rodents, myelination occurs predominantly during the first month of life (17Muse E.D. Jurevics H. Toews A.D. Matsushima G.K. Morell P. Parameters related to lipid metabolism as markers of myelination in mouse brain.J. Neurochem. 2001; 76: 77-86Crossref PubMed Scopus (83) Google Scholar). The magnitude of the tasks that glial cells have to accomplish in a short period of time is easily appreciated when visualizing the membrane expansion taking place during myelination (Fig. 1). In rodents, it has been estimated that the myelin-membrane surface area of one glial cell expands at a rate of 5–50 × 103μm2/day, compared with the surface area of the cell soma (i.e., the plasma membrane) of ∼ 0.3 × 103μm2 (18Baron W. Hoekstra D. On the biogenesis of myelin membranes: sorting, trafficking and cell polarity.FEBS Lett. 2009; 584: 1760-1770Crossref PubMed Scopus (83) Google Scholar). This corresponds to an estimated 6,500-fold increase in membrane surface between an immature and a fully myelinated oligodendrocyte (19Webster H.D. The geometry of peripheral myelin sheaths during their formation and growth in rat sciatic nerves.J. Cell Biol. 1971; 48: 348-367Crossref PubMed Google Scholar). In rodents, the expansion of the myelin membrane correlates with substantial accumulation of cholesterol and lipids in both the developing CNS and PNS (17Muse E.D. Jurevics H. Toews A.D. Matsushima G.K. Morell P. Parameters related to lipid metabolism as markers of myelination in mouse brain.J. Neurochem. 2001; 76: 77-86Crossref PubMed Scopus (83) Google Scholar, 20Heape A. Juguelin H. Fabre M. Boiron F. Garbay B. Fournier M. Bonnet J. Cassagne C. Correlation between the morphology and the lipid and protein compositions in the peripheral nervous system of individual 8-day-old normal and trembler mice.Brain Res. 1986; 390: 173-180Crossref PubMed Scopus (19) Google Scholar, 21Heape A. Juguelin H. Fabre M. Boiron F. Cassagne C. A quantitative developmental study of the peripheral nerve lipid composition during myelinogenesis in normal and trembler mice.Brain Res. 1986; 390: 181-189Crossref PubMed Scopus (33) Google Scholar, 22Heape A. Boiron F. Cassagne C. A developmental study of fatty acyl group contents in the peripheral nervous system of normal and trembler mice.Neurochem. Pathol. 1987; 7: 157-167Crossref PubMed Scopus (14) Google Scholar). More recently, transcriptional profiling of developing peripheral nerves shed light on the molecular cascades involved in PNS myelin assembly (23Nagarajan R. Le N. Mahoney H. Araki T. Milbrandt J. Deciphering peripheral nerve myelination by using Schwann cell expression profiling.Proc. Natl. Acad. Sci. USA. 2002; 99: 8998-9003Crossref PubMed Scopus (104) Google Scholar, 24Verheijen M.H. Chrast R. Burrola P. Lemke G. Local regulation of fat metabolism in peripheral nerves.Genes Dev. 2003; 17: 2450-2464Crossref PubMed Scopus (133) Google Scholar). It was observed that transcripts encoding structural myelin proteins and enzymes involved in myelin lipid biosynthesis were expressed in a highly synchronized and timely fashion, suggesting a strict control of a balanced and local production of these two key components of myelin assembly. Relatively little is known about myelin lipid turnover in vivo, but studies in mice indicate a necessity to renew myelin lipids in adult life (25Ando S. Tanaka Y. Toyoda Y. Kon K. Turnover of myelin lipids in aging brain.Neurochem. Res. 2003; 28: 5-13Crossref PubMed Scopus (62) Google Scholar).MYELIN DEFECTS IN INHERITED DISEASES AFFECTING LIPID METABOLISMThe lipid-rich composition of myelin is likely to contribute to the frequent occurrence of myelin defects in lipid metabolism disorders, including hypomyelination (decreased myelin production), dysmyelination (abnormally formed myelin), and demyelination (degenerative loss of myelin). Inherited forms of these diseases are particularly informative and provide direct insight into the underlying molecular mechanisms. These involve defects in metabolism of all myelin enriched lipids: cholesterol, glycosphingolipid, and long-chain fatty acids (Table 2). In several of these disorders the defects are caused by lipotoxicity, a result of the accumulation of various metabolic precursors involved in lipid biosynthesis to levels that are toxic to the myelinating glial cells or at least interfere with normal myelin membrane structure [reviewed in (26Dyck P.J. Thomas P.K. Lysosomal and peroxisomal disorders. In, Peripheral Neuropathy. Elsevier Saunders, Philadelphia, PA2005: 1845-1882Google Scholar, 27Wanders R.J. Ferdinandusse S. Brites P. Kemp S. Peroxisomes, lipid metabolism and lipotoxicity.Biochim. Biophys. Acta. 2010; 1801: 272-280Crossref PubMed Scopus (104) Google Scholar, 28Horster F. Surtees R. Hoffmann G.F. 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Here, we will particularly discuss the disorders in which myelin defects are more likely caused by a primary defect in myelinating glia that causes reduced levels of myelin-enriched lipids, and are therefore more informative as to the contribution of these lipids to the synthesis and function of myelin under normal and pathological conditions (see section 'Why are myelinating glial cells particularly vulnerable to lipid metabolism disorders?’).TABLE 2Inherited lipid disorders with myelin abnormalitiesPresumed Incidence or Number of PatientsGeneral Clinical FeaturesMyelin DefectDiseaseOMIM#InheritanceMutated GeneFunctionOnsetCNSPNSRemarksSmith-Lemli-Opitz syndrome270400Autosomal recessive1-2:40,000sterol delta-7-reductasecholesterol metabolismmicrocephaly mental retardation hypotoniamicrognathia polydactyly ambiguous genitalia cleft palatemostly within the first month of life (early lethality is common)+++- absence or hypoplasia of corpus callosum detected- reduced NCV in PNS (rare)Cerebrotendinous xanthomatosis213700Autosomal recessive1:50,000 (166Lorincz M.T. Rainier S. Thomas D. Fink J.K. Cerebrotendinous xanthomatosis: possible higher prevalence than previously recognized.Arch. Neurol. 2005; 62: 1459-1463Crossref PubMed Scopus (75) Google Scholar)sterol 27-hydroxylasecholesterol metabolismtendon xanthomas mental retardation cerebellar ataxia spasticity cataractsvariable (6 to 60 years)++++- diffuse or focal cerebral and cerebellar white matter disease detected- reduced NCV in PNSTangier disease205400Autosomal recessive∼100 patients (167Brunham L.R. Singaraja R.R. Hayden M.R. Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis.Annu. Rev. 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Harzer K. Hunneman D.H. Kohler W. Kurlemann G. Kohlschutter A. Leukodystrophy incidence in Germany.Am. J. Med. Genet. 1997; 71: 475-478Crossref PubMed Scopus (0) Google Scholar, 169Gustavson K.H. Hagberg B. The incidence and genetics of metachromatic leucodystrophy in northern Sweden.Acta Paediatr. Scand. 1971; 60: 585-590Crossref PubMed Google Scholar)arylsulfatase Asphingolipid metabolismataxia muscle weakness optic atrophy mental deterioration white matter abnormalities peripheral neuropathyvariable (late infantile to adult onset)++++++- hyperintensities detected in white matter- reduced NCV in PNSKrabbe disease245200Autosomal recessive1:100,000galactosylceramidasesphingolipid metabolismdevelopmental regression hyperirritability seizuresoptic atrophyvariable, but 90% within first 6 months of life (in this case the lethality before the age of 2 years is common)++++++- diffuse cerebral atrophy detected- reduced NCV in PNSNiemann-Pick disease type A257200Autosomal recessive0.5-1:100,000 (general population)3:100,000 (Ashkenazi Jews) (170Schuchman E.H. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease.J. Inherit. Metab. 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Pyruvate carboxylase deficiency: prenatal onset of ischemia-like brain lesions in two sibs with the acute neonatal form.Am. J. Med. Genet. 1999; 84: 94-101Crossref PubMed Scopus (0) Google Scholar)pyruvate carboxylase genelipogenesishepatomegaly mental retardation psychomotor retardation lactic acidemiaOnset at birth or in early infancy+++- white matter changes detectedInformation provided is based on OMIM database (www.ncbi.nlm.nih.gov/omim/), additional references on presumed incidence, and references on myelin defects as provided in the text. Open table in a new tab Cholesterol disordersAt least three different cholesterol-related disorders cause defects in myelin (Table 2). Of these, Cerebrotendinous xanthomatosis (CTX) and Tangier disease (TD) lead to accumulation of 7α-hydroxy-4-cholesten-3-one and cholestanol (in CTX) and cholesterolesters (in TD), which are likely to underlie the myelin pathology [(29Verrips A. Hoefsloot L.H. Steenbergen G.C. Theelen J.P. Wevers R.A. 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