Specific downregulation and mistargeting of the lipid raft-associated protein MAL in a glycolipid storage disorder

Saravanan, Konda Mani; Schaeren‐Wiemers, Nicole; Klein, Diana; Sandhoff, Roger; Schwarz, Andreas; Yaghootfam, Afshin; Gieselmann, Volkmar; Franken, Sebastian

doi:10.1016/j.nbd.2004.03.008

Cited by 46 publications

(63 citation statements)

References 52 publications

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“…5F ). In addition, we examined expression levels of the MAL protein, which has been found to be differentially expressed in several mouse lines exhibiting changes in the GalC and/or sulfatide level (Saravanan et al, 2004;Fewou et al, 2005). MAL expression levels were not significantly different between FA2H Ϫ/Ϫ and FA2H ϩ/ϩ mice (Fig.…”

Section: Normal Oligodendrocyte Differentiation In Fa2hmentioning

confidence: 99%

Absence of 2-Hydroxylated Sphingolipids Is Compatible with Normal Neural Development But Causes Late-Onset Axon and Myelin Sheath Degeneration

Zöller¹,

Meixner²,

Hartmann³

et al. 2008

J. Neurosci.

156

134

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Sphingolipids containing 2-hydroxylated fatty acids are among the most abundant lipid components of the myelin sheath and therefore are thought to play an important role in formation and function of myelin. To prove this hypothesis, we generated mice lacking a functional fatty acid 2-hydroxylase (FA2H) gene. FA2H-deficient (FA2H Ϫ/Ϫ ) mice lacked 2-hydroxylated sphingolipids in the brain and in peripheral nerves. In contrast, nonhydroxylated galactosylceramide was increased in FA2H Ϫ/Ϫ mice. However, oligodendrocyte differentiation examined by in situ hybridization with cRNA probes for proteolipid protein and PDGF␣ receptor and the time course of myelin formation were not altered in FA2H Ϫ/Ϫ mice compared with wild-type littermates. Nerve conduction velocity measurements of sciatic nerves revealed no significant differences between FA2H Ϫ/Ϫ and wild-type mice. Moreover, myelin of FA2H Ϫ/Ϫ mice up to 5 months of age appeared normal at the ultrastructural level, in the CNS and peripheral nervous system. Myelin thickness and g-ratios were normal in FA2H Ϫ/Ϫ mice. Aged (18-month-old) FA2H Ϫ/Ϫ mice, however, exhibited scattered axonal and myelin sheath degeneration in the spinal cord and an even more pronounced loss of stainability of myelin sheaths in sciatic nerves. These results show that structurally and functionally normal myelin can be formed in the absence of 2-hydroxylated sphingolipids but that its long-term maintenance is strikingly impaired. Because axon degeneration appear to start rather early with respect to myelin degenerations, these lipids might be required for glial support of axon function.

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Section: Normal Oligodendrocyte Differentiation In Fa2hmentioning

confidence: 99%

Absence of 2-Hydroxylated Sphingolipids Is Compatible with Normal Neural Development But Causes Late-Onset Axon and Myelin Sheath Degeneration

Zöller¹,

Meixner²,

Hartmann³

et al. 2008

J. Neurosci.

156

134

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“…Primary OLGs 1 to 2-days-old rat brain OLGs 12 DIV TX-100 0.5% 3 min RT Wilson and Brophy 1989 30-days-old rat brain TX-100 1% 30 min 4°C Kim and Pfeiffer 2002 Adult rat brain CHAPS 20 mM 2h 4°C Kim et al 1995 Purified myelin 2-year-old mice TX-100 2% 30 min 4°C Saravanan et al 2004 Primary OLGs Mature rat OLGs CHAPS 40 mM 30 min 4°C Kim et al 1995 …”

Section: Mbpmentioning

confidence: 99%

“…Spinal cord Rat (WT or EAE) Lubrol WX 0.5% 30 min 4°C Maier et al 2005 Cx-32 Purified myelin 30-days-old rat brain TX-100 1% 30 min 4°C/37°C Kim and Pfeiffer 1999 30-days-old rat brain TX-100 1% 30 min 4°C Kim and Pfeiffer 1999 OSP Purified myelin 35-days-old mice TX-100 / CHAPS Brij 96V / TX-102 1% 30 min 4°C Taylor et al 2002 30-days-old rat brain TX-100 1% 30 min 4°C Kim and Pfeiffer 1999 35-days-old mice TX-100/CHAPS Brij 96V/TX-102 1% 30 min 4°C Taylor et al 2002 4-months-old mice: WT and MAL KO CHAPS na 30 min 4°C Schaeren-Wiemers et al 2004 Adult mouse brain CHAPS 20 mM 30 min 4°C 2-year-old mice TX-100 2% 30 min 4°C Saravanan et al 2004 Purified myelin Bovine brain E20 -E40 CHAPS 1.5% 30 min 4°C Debruin et al 2005 …”

Section: Magmentioning

confidence: 99%

“…Mouse OLG 5 DIV CHAPS 20 mM 30 min 4°C 30-days-old rat TX-100 1% 30 min 4°C Kim and Pfeiffer 1999 4-6 weeks old rat TX-100 0.5% 3 min RT Gillespie et al 1989 35-days-old mice TX-100 / CHAPS / Brij 96V / TX-102 1% 30 min 4°C/37°C Taylor et al 2002 2-year-old mice TX-100 2% 30 min 4°C Saravanan et al 2004 TX-100 1% na 4°C Mouse CHAPS 30 mM na 4°C Boyanapalli et al 2005 Rabbit TX-100 1% 16h + 24h 4°C Pereyra et al 1988 Purified myelin Bovine brain E11 -E40 CHAPS 1.5% 30 min 4°C Debruin et al 2005 Primary OLGs 1-2 day old rat brain OLGs 12 DIV TX-100 0.5% 3 min RT Wilson and Brophy 1989 CNP Optic nerve p13, p18, p24 and 2 months old rat TX-100 1% 1h 4°C Maier et al 2005 Primary OLGs premyelinating mouse OLGs TX-100 1% 1h 4°C Schafer et al 2004 TX-100 1% 30 min 4°C Spinal cord Rat (WT or EAE) Lubrol WX 0.5% 30 min 4°C Maier et al 2005 Optic nerve p13, p18, p24 and 2 months old rat TX-100 1% 1h 4°C Schafer et al 2004 35-days-old mice TX-100 / CHAPS / Brij 96V / TX-102 1% 30 min 4°C Taylor et al 2002 Adult mouse brain TX-100 2% 30 min 4°C Krämer et al 1997Krämer et al , 1999 Purified myelin 2-year-old mice TX-100 2% 30 min 4°C Saravanan et al 2004 Mouse OLGs 5/8 DIV TX-100 2% 30 min 4°C Krämer et al 1997Krämer et al , 1999 Primary OLGs Mouse OLG 5 DIV CHAPS 20 mM 30 min 4°C NCAM 120…”

Section: Primary Olgsmentioning

confidence: 99%

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Rafts in oligodendrocytes: Evidence and structure–function relationship

Gielen

Baron

vandeVen

et al. 2006

Glia

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“…One reason for this discrepancy between human patients and mice could be that Sulfs accumulate to a much smaller extent in the brain of ARSA knockout mice than in the brain of MLD patients. 8 However, it is also possible that environmental and genetic factors are implicated in the onset and severity of the human disease. Nevertheless, the ARSA knockout mouse is an appropriate model for the investigation of therapeutic interventions.…”

Section: Introductionmentioning

confidence: 99%

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer

et al. 2006

Self Cite

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Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of arylsulfatase A (ARSA) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (PNS) and central nervous system (CNS), and early death of MLD patients. The ARSA knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the PNS and CNS. We showed that adeno-associated virus serotype 5-mediated gene transfer in the brain of ARSA knockout mice reverses Sulf storage and prevents neuropathological abnormalities and neuromotor disabilities when vector injections are performed at a pre-symptomatic stage of disease. Direct injection of viral particles into the brain of ARSA knockout mice at a symptomatic stage results in sustained expression of ARSA, prevention of Sulf storage and neuropathological abnormalities. Despite these significant corrections, the treated mice continue to develop neuromotor disability. We show that more subtle biochemical abnormalities involving gangliosides and galactocerebroside are in fact not corrected.

show abstract

Specific downregulation and mistargeting of the lipid raft-associated protein MAL in a glycolipid storage disorder

Cited by 46 publications

References 52 publications

Absence of 2-Hydroxylated Sphingolipids Is Compatible with Normal Neural Development But Causes Late-Onset Axon and Myelin Sheath Degeneration

Absence of 2-Hydroxylated Sphingolipids Is Compatible with Normal Neural Development But Causes Late-Onset Axon and Myelin Sheath Degeneration

Rafts in oligodendrocytes: Evidence and structure–function relationship

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer

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