title: Aberrant production of tenascin-C in globoid cell leukodystrophy alters psychosine-induced microglial functions.
abstract: Globoid cell leukodystrophy (GLD), or Krabbe disease, is a rare and often fatal demyelinating disease caused by mutations in the galactocerebrosidase (galc) gene that result in accumulation of galactosylsphingosine (psychosine). We recently reported that the extracellular matrix (ECM) protease, matrix metalloproteinase-3, is elevated in GLD and that it regulates psychosine-induced microglial activation. Here, we examined central nervous system ECM component expression in human GLD patients and in the twitcher mouse model of GLD using immunohistochemistry. The influence of ECM proteins on primary murine microglial responses to psychosine was evaluated using ECM proteins as substrates and analyzed by quantitative real-time polymerase chain reaction, immunocytochemistry, and ELISA. Functional analysis of microglial cytotoxicity was performed on oligodendrocytes in coculture, and cell death was measured by lactose dehydrogenase assay. Tenascin-C (TnC) was expressed at higher levels in human GLD and in twitcher mice versus controls. Microglial responses to psychosine were enhanced by TnC, as determined by an increase in globoid-like cell formation, matrix metalloproteinase-3 mRNA expression, and higher toxicity toward oligodendrocytes in culture. These findings were consistent with a shift toward the M1 microglial phenotype in TnC-grown microglia. Thus, elevated TnC expression in GLD modified microglial responses to psychosine. These data offer a novel perspective and enhance understanding of the microglial contribution to GLD pathogenesis.
authors.affiliation: From the Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut (KIC, PNW, KMJ, AMN, AWG, AVS, EB, SJC); Stem Cells and Regenerative Biology Program, Sanford-Burnham Institute, La Jolla, California (EYS); and Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois (ERB).
authors.forename: Kumiko I
authors.initials: KI
authors.lastname: Claycomb
authors.forename: Paige N
authors.initials: PN
authors.lastname: Winokur
authors.forename: Kasey M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Nicaise
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Giampetruzzi
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Sacino
authors.forename: Evan Y
authors.initials: EY
authors.lastname: Snyder
authors.forename: Elisa
authors.initials: E
authors.lastname: Barbarese
authors.forename: Ernesto R
authors.initials: ER
authors.lastname: Bongarzone
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Crocker
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D002675:Child, Preschool; D018920:Coculture Techniques; D006801:Humans; D007223:Infant; D007965:Leukodystrophy, Globoid Cell / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D011609:Psychosine / Q000494:pharmacology*; D019063:Tenascin / Q000096:biosynthesis*
chemical_list: D019063:Tenascin; D011609:Psychosine