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Secondary Alterations of Sphingolipid Metabolism in Lysosomal Storage Diseases

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Abstract

In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal membrane sphingolipid patterns and altered plasma membrane organization. In this paper, we review the potential importance of these alterations to the pathogenesis of these diseases and focus the reader’s attention on some secondary alterations of sphingolipid metabolism that have been sporadically reported in the literature. Moreover, we present a detailed analysis of the lipid composition of different central nervous system and extraneural tissues from the acid sphingomyelinase-deficient mouse, the animal model for Niemann-Pick disease type A, characterized by the accumulation of sphingomyelin. Our data show an unexpected, tissue specific selection of the accumulated molecular species of sphingomyelin, and an accumulation of GM3 and GM2 gangliosides in both neural and extraneural tissues, that cannot be solely explained by the lack of acid sphingomyelinase.

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Abbreviations

ASMKO:

Acid sphingomyelinase knockout

CNS:

Central nervous system

ER:

Endoplamic reticulum

GD:

Gaucher disease

GlcCer:

Glucosylceramide

GSL:

Glycosphingolipids

HPTLC:

High performance thin layer chromatography

NPD:

Niemann-Pick disease

PC:

Phosphatidylcholine

PE:

Phosphatidylethanolamine

SL:

Sphingolipids

SM:

Sphingomyelin

WT:

Wild-type

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Acknowledgments

This paper has been supported by University of Milan Grant 2006-08 to S.S., Fondazione Cariplo Grant 2006 to S.S, and by Mizutani Foundation for Glycosciences Grant 2007 to A.P. E.H.S. is the recipient of grants from the National Institutes of Health (DK54830 and HD28750).

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Authors and Affiliations

  1. Department of Medical Chemistry, Biochemistry and Biotechnology, Center of Excellence on Neurodegenerative Diseases, University of Milan, Via Fratelli Cervi 93, 20090, Segrate, Italy

    Alessandro Prinetti, Simona Prioni, Elena Chiricozzi, Vanna Chigorno & Sandro Sonnino

  2. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, Icahn Medical Institute, New York, NY, 10029, USA

    Edward H. Schuchman

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  1. Alessandro Prinetti
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  2. Simona Prioni
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  3. Elena Chiricozzi
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  4. Edward H. Schuchman
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  5. Vanna Chigorno
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  6. Sandro Sonnino
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Correspondence to Alessandro Prinetti.

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Special Issue: In Honor of Dr. Abel Lajtha.

Simona Prioni and Elena Chiricozzi are equally contributed to the work.

Appendix: Experimental Procedures

Appendix: Experimental Procedures

Materials

Commercial chemicals were of the highest purity available, common solvents were distilled before use and water was doubly distillated in a glass apparatus. Lipids to be used as standard were extracted from rat brain, purified [124], and structurally characterized [125]. HPTLC plates were from Merck (Darmstadt, Germany). RC DC™ protein assay kit was from Bio-Rad (Hercules,CA,USA). Bovin serum albumin was from Sigma–Aldrich (St. Louis, MO).

Animals

The ASMKO mouse model [109] was backcrossed onto the C57BL/6 N strain at the Charles River Laboratory, Milan, Italy. Starting from heterozygous mice, homozygous mice colonies were established: WT mice (C57BL/6 N; ASM +/+) used as control and mutant (ASMKO) mice (C57BL/6 N; ASM-/-). Mice were bred according to the NIH Guide for the Care and Use of Laboratory Animals. Genotypes were checked by PCR [109]. Mutants and control mice were killed with CO2.

Tissue Lipid Analysis

Tissues from ASMKO and WT mice were weighed and homogenized in iced Millipore water (500 mg of fresh tissue/mL); For lipid analysis we extracted the whole tissue from a single animal. The homogenates were sonicated at ice temperature, snap-frozen and lyophilized; lipids were extracted with chloroform/methanol/water 20:10:1 (v/v/v) three times. Total lipid extracts were subjected to a two-phase partitioning leading to the separation of an aqueous phase containing gangliosides and an organic phase containing all the other lipids [126]. The ganglioside content of each total tissue was determined in the aqueous phases as lipid-bound sialic acid using the resorcinol method [127], while the phospholipid content was determined as phosphate in the organic phases following perchloric acid digestion using the method of Bartlett [128]. The SM content was determined in the organic phase after alkaline treatment.

Lipids were separated by monodimensional HPTLC carried out using the following solvent systems: chloroform/methanol/0.2% calcium chloride 60:35:8 (v/v/v) for phospholipids and SM, hexane/ethyl-acetate 3:2 (v/v) for cholesterol, and chloroform/methanol/0.2% calcium chloride 50:42:11 (v/v/v) for gangliosides.

Separated lipids were identified on the basis of co-migration with lipid standards [68].

Phospholipids were detected by spraying the TLC with a molybdate reagent [129]. Cholesterol was visualized by spraying the TLC with anisaldehyde and quantified by densitometry and comparison with 0.1–0.2 μg of a standard compound [68]. SM was recognized using 15% concentrated sulfuric acid in 1-butanol [68]. Gangliosides were visualized after separation on HPTLC by specific detection with the p-dimethylaminobenzaldehyde reagent [130].

The relative amounts of lipids associated with each band after HPTLC separation were determined by densitometry using the Molecular Analyst program (Bio-Rad Laboratories, Hercules, CA, USA). The number of sialyl residues was taken into account for analysis of ganglioside content. The mass content of each phospholipid, or ganglioside, was calculated on the basis of the percentage distribution of total phospholipid or ganglioside content, determined as described above [8, 68]. The protein content was determined in all samples using the RC DC™ protein assay and BSA as the reference standard.

Statistical Analysis

Experiments were performed on three different tissue samples from different animals for each genotype and age group. The results are expressed as mean value ± SD Statistical analysis of the data was performed by one-way ANOVA followed by the Student–Newman–Keuls’ test. p < 0.05 was considered significant (compared with WT) and p values are indicated in the legend of each figure and/or table.

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Prinetti, A., Prioni, S., Chiricozzi, E. et al. Secondary Alterations of Sphingolipid Metabolism in Lysosomal Storage Diseases. Neurochem Res 36, 1654–1668 (2011). https://doi.org/10.1007/s11064-010-0380-3

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