MMP-3 Mediates Psychosine-Induced Globoid Cell Formation: Implications for Leukodystrophy Pathology

摘要: Globoid cell leukodystrophy (GLD) or Krabbe disease, is a fatal demyelinating disease attributed to mutations in the galactocerebrosidase (GALC) gene. Loss of function GALC result accumulation glycolipid intermediate, galactosylsphingosine (psychosine). Due cytotoxicity psychosine, it has been hypothesized that accumulated psychosine underlie pathophysiology GLD. However, cellular mechanisms GLD remain unclear. cells, multinucleated microglia/macrophages central nervous system (CNS), are defining characteristic Here we report exposure primary glial cultures induces expression and production matrix metalloproteinase (MMP)-3 mediated morphological transformation microglia into globoid type. Additionally, psychosine-induced formation from was prevented by either genetic ablation chemical inhibition MMP-3. These effects microglia-specific as peripheral macrophages exposed did not become activated express increased levels In brain twitcher mice, murine model human GLD, elevated MMP-3 relative wild-type littermates contemporaneous with onset further progression. Further, bone marrow transplantation (BMT), currently only therapeutically beneficial treatment for mitigate mice. Hence, may promote microglial responses represent an important pathophysiological process this its treatment.