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MBC in Press, published online ahead of print November 21, 2007
Mol. Biol. Cell 10.1091/mbc.E07-05-0439

A more recent version of this article appeared on February 1, 2008
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Submitted on May 11, 2007
Revised on October 29, 2007
Accepted on November 9, 2007

Anomalous Surface Distribution of GPI-anchored Proteins in Neurons Lacking Acid Sphingomyelinase

Cristian Galvan,*{dagger} Paola G. Camoletto,*{dagger}{ddagger}{sect}|| Flavio Cristofani,* Paul P. Van Veldhoven,|| and Maria Dolores Ledesma*{ddagger}{sect}

*Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (Torino), Italy; {ddagger}Department of Molecular and Developmental Genetics, Flanders Institute for Biotechnology, 3000 Leuven, Belgium; {sect}Center for Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; ||Department of Molecular Cell Biology, LIPIT, Katholieke Universiteit Leuven, 3000 Leuven, Belgium

Monitoring Editor: Sean Munro

Acid sphingomyelinase (ASM) converts sphingomyelin (SM) into ceramide. Mutations in the ASM gene cause the mental retardation syndrome Niemann Pick type A (NPA) characterized as a lysosomal disorder because of the SM accumulation in these organelles. We here report that neurons from mice lacking ASM (ASMKO) present increased plasma membrane SM levels evident in detergent resistant membranes. Paralleling this lipidic alteration, GPI-anchored proteins show an aberrant distribution in both axons and dendrites instead of the axonal enrichment observed in neurons from wild type mice. Trafficking analysis suggests that this is due to defective internalization from dendrites. Increasing the SM content in wild type neurons mimics these defects while SM reduction in ASMKO neurons prevents their occurrence. Moreover, expression of active RhoA, which membrane attachment is affected by SM accumulation, rescues internalization rates in ASMKO neurons. These data unveil an unexpected role for ASM in neuronal plasma membrane organization and trafficking providing insight on the molecular mechanisms involved. They also suggest that deficiencies in such processes could be key pathological events in NPA disease. Keywords: sphingomyelin; lipid microdomains; Niemann Pick type A; GPI-anchored proteins; endocytosis.

{dagger}These authors contributed equally to this work.

Address correspondence to: Maria Dolores Ledesma (lola.ledesma{at}med.kuleuven.be)






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