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Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat

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Abstract

The high concentration of N-acetylaspartate (NAA) in neurons of the central nervous system and its growing clinical use as an indicator of neuronal viability has intensified interest in the biological function of this amino acid derivative. The biomedical relevance of such inquiries is highlighted by the myelin-associated pathology of Canavan disease, an inherited childhood disorder resulting from mutation of aspartoacylase (ASPA), the NAA-hydrolyzing enzyme. This enzyme is known to be localized in oligodendrocytes with bimodal distribution in cytosol and the myelin sheath, and to produce acetyl groups utilized in myelin lipid synthesis. Loss of this acetyl source in Canavan disease and rodent models such as the tremor rat are thought to account for the observed myelin deficit. This study was undertaken to further define and quantify the specific lipid abnormalities that occur as a result of ASPA deficit in the tremor rat. Employing mass spectrometry together with high performance thin-layer chromatography, we found that myelin from 28-day-old animals showed major reduction in cerebrosides (CB) and sulfatides (Sulf) with unsubstituted fatty acids, and equal if not greater changes in myelin from 7-month-old tremors. Cerebrosides with 2-hydroxyfatty acids showed little if any change at either age; Sulf with 2-hydroxyfatty acids showed no significant change at 28 days, but surprisingly a major increase at 7 months. Two species of phosphatidylcholine, 32:0 and 34:1, also showed significant increase, but only at 28 days. One form of phosphatidylethanolamine, PE36:1, was reduced a modest amount at both ages, whereas the plasmalogen form did not change. The dysmyelination that results from inactivation of ASPA is thus characterized by selective decreases as well as some increases in specific lipids.

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Abbreviations

ASPA:

Aspartoacylase

BHT:

2,6-di-tert-butyl-4-methylphenol

C:

Chloroform

CB:

Cerebrosides

CNS:

Central nervous system

EPG:

Ethanolamine phosphoglyceride

HT:

Heterozygote

HPTLC:

High performance thin-layer chromatography

MALDI-TOFMS:

Matrix-assisted laser desorption/ionization—time of flight mass spectrometry

M:

Methanol

NAA:

N-acetylaspartate

PC:

Phosphatidylcholine

PE:

Phosphatidylethanolamine

PI:

Phosphatidylinositol

PS:

Phosphatidylserine

Sulf:

Sulfatide

TM:

Tremor rat

WT:

Wild type

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Acknowledgements

This work was supported by grants from the National Multiple Sclerosis Society, PP1008 (RWL), Jacob’s Cure: A Fight Against Canavan Disease (RWL), and The National Institutes of Health, USA, NS046593 (HL). We are grateful to the National BioResource Project for the Rat in Japan (http://www.anim.med.kyoto-u.ac.jp/NBR/) for providing tremor rats.

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Authors and Affiliations

  1. Department of Neurology and Neurosciences, New Jersey Medical School, UMDNJ, 185 So. Orange Ave., MSB-H506, Newark, NJ, 07103, USA

    Jianfeng Wang, Gusheng Wu & Robert W. Ledeen

  2. Department of Surgery, Robert Wood Johnson Medical School, UMDNJ, Camden, NJ, 08103, USA

    Paola Leone

  3. Department of Molecular Genetics, Robert Wood Johnson Medical School, UMDNJ, Camden, NJ, 08103, USA

    Paola Leone & Jeremy S. Francis

  4. Department of Biochemistry and Molecular Biology, New Jersey Medical School, UMDNJ, 185 So. Orange Ave., Newark, NJ, 07103, USA

    Hong Li & Mohit Raja Jain

  5. Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan

    Tadao Serikawa

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  1. Jianfeng Wang
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Correspondence to Robert W. Ledeen.

Additional information

Special issue article in honor of Dr. George DeVries.

Fatty acid designations (e.g. 18:1) indicate carbon number and number of double bonds.

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Wang, J., Leone, P., Wu, G. et al. Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat. Neurochem Res 34, 138–148 (2009). https://doi.org/10.1007/s11064-008-9726-5

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  • DOI: https://doi.org/10.1007/s11064-008-9726-5

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