Aberrant production of tenascin-C in globoid cell leukodystrophy alters psychosine-induced microglial functions.

[krabbe disease]

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 M 1 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 .

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