title: Acid sphingomyelinase (aSMase) deficiency leads to abnormal microglia behavior and disturbed retinal function.
abstract: Mutations in the acid sphingomyelinase (aSMase) coding gene sphingomyelin phosphodiesterase 1 (SMPD1) cause Niemann-Pick disease (NPD) type A and B. Sphingomyelin storage in cells of the mononuclear phagocyte system cause hepatosplenomegaly and severe neurodegeneration in the brain of NPD patients. However, the effects of aSMase deficiency on retinal structure and microglial behavior have not been addressed in detail yet. Here, we demonstrate that retinas of aSMase(-/-) mice did not display overt neuronal degeneration but showed significantly reduced scotopic and photopic responses in electroretinography. In vivo fundus imaging of aSMase(-/-) mice showed many hyperreflective spots and staining for the retinal microglia marker Iba1 revealed massive proliferation of retinal microglia that had significantly enlarged somata. Nile red staining detected prominent phospholipid inclusions in microglia and lipid analysis showed significantly increased sphingomyelin levels in retinas of aSMase(-/-) mice. In conclusion, the aSMase-deficient mouse is the first example in which microglial lipid inclusions are directly related to a loss of retinal function.
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Dannhausen
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Karlstetter
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Caramoy
authors.affiliation: Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Volz
authors.affiliation: Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Jägle
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.affiliation: Institute for Medical Microbiology, Immunology and Hygiene and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
authors.affiliation: Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Cologne, Germany. Electronic address: thomas.langmann@uk-koeln.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Langmann
mesh_terms: D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism; D012160:Retina / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*
chemical_list: D010743:Phospholipids; D013108:Sphingomyelin Phosphodiesterase
keywords: Acid sphingomyelinase; Inflammation; Lipid accumulation; Microglia; Niemann-Pick disease; Retina