title: Anomalous surface distribution of glycosyl phosphatidyl inositol-anchored proteins in neurons lacking acid sphingomyelinase.
abstract: 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, whereas 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.
authors.affiliation: Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, A.O. San Luigi Gonzaga, Regione Gonzole 10, 10043 Orbassano (Torino), Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Galvan
authors.forename: Paola G
authors.initials: PG
authors.lastname: Camoletto
authors.forename: Flavio
authors.initials: F
authors.lastname: Cristofani
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Ledesma
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D016764:Cell Polarity / Q000187:drug effects; D003902:Detergents / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005089:Exocytosis / Q000187:drug effects; D005677:G(M1) Ganglioside / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D011328:Prions / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency* / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D003902:Detergents; D017261:Glycosylphosphatidylinositols; D011328:Prions; D013109:Sphingomyelins; D005677:G(M1) Ganglioside; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase; D020742:rhoA GTP-Binding Protein