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Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders

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Abstract

Sphingolipids are polar membrane lipids present as minor components in eukaryotic cell membranes. Sphingolipids are highly enriched in nervous cells, where they exert important biological functions. They deeply affect the structural and geometrical properties and the lateral order of cellular membranes, modulate the function of several membrane-associated proteins, and give rise to important intra- and extracellular lipid mediators. Sphingolipid metabolism is regulated along the differentiation and development of the nervous system, and the expression of a peculiar spatially and temporarily regulated sphingolipid pattern is essential for the maintenance of the functional integrity of the nervous system: sphingolipids in the nervous system participate to several signaling pathways controlling neuronal survival, migration, and differentiation, responsiveness to trophic factors, synaptic stability and synaptic transmission, and neuron–glia interactions, including the formation and stability of central and peripheral myelin. In several neurodegenerative diseases, sphingolipid metabolism is deeply deregulated, leading to the expression of abnormal sphingolipid patterns and altered membrane organization that participate to several events related to the pathogenesis of these diseases. The most impressive consequence of this deregulation is represented by anomalous sphingolipid–protein interactions that are at least, in part, responsible for the misfolding events that cause the fibrillogenic and amyloidogenic processing of disease-specific protein isoforms, such as amyloid β peptide in Alzheimer’s disease, huntingtin in Huntington’s disease, α-synuclein in Parkinson’s disease, and prions in transmissible encephalopathies. Targeting sphingolipid metabolism represents today an underexploited but realistic opportunity to design novel therapeutic strategies for the intervention in these diseases.

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Abbreviations

AD:

Alzheimer’s disease

CJD:

Creutzfeldt–Jakob disease

CNS:

Central nervous system

GalCer:

Galactosylceramide

GD:

Gaucher disease

GlcCer:

Glucosylceramide

GPL:

Glycerophospholipids

GSL:

Glycosphingolipids

HD:

Hungtington’s disease

MAG:

Myelin-associated glycoprotein

NPD:

Niemann–Pick disease

PD:

Parkinson’s disease

PNS:

Peripheral nervous system

PrP:

Prion protein

SL:

Sphingolipids

SM:

Sphingomyelin

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Acknowledgements

This paper has been supported by University of Milan Grant 2006 to S. S., Fondazione Cariplo Grant 2006 to S. S., and by Mizutani Foundation for Glycosciences Grant 2007 to A. P.

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Authors and Affiliations

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

    Federica Scandroglio, Simona Prioni, Nicoletta Loberto, Massimo Aureli, Vanna Chigorno, Sandro Sonnino & Alessandro Prinetti

  2. Section of Biochemistry, Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy

    Marco Piccinini, Barbara Buccinnà, Elisa Lupino, Giovanni DeMarco, Annarosa Lomartire & Maria Teresa Rinaudo

  3. Dipartimento di Chimica, Biochimica e Biotecnologie per la Medicina, Università degli Studi di Milano, Via Fratelli Cervi 93, 20090, Segrate, Italy

    Alessandro Prinetti

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Correspondence to Alessandro Prinetti.

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Piccinini, M., Scandroglio, F., Prioni, S. et al. Deregulated Sphingolipid Metabolism and Membrane Organization in Neurodegenerative Disorders. Mol Neurobiol 41, 314–340 (2010). https://doi.org/10.1007/s12035-009-8096-6

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  • DOI: https://doi.org/10.1007/s12035-009-8096-6

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