Establishment of new therapeutic strategies for neurogenetic disorders during childhood

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Gaucher disease (GD), caused by a defect of β-glucosidase (β-Glu), is the most common form of sphingolipidosis. We found that a carbohydrate mimic β-octyl-β-valienamine (NOV), an inhibitor of β-Glu, could increase the protein level and enzyme activity of F213I, N188S, G202R and N370S mutant forms of β-Glu in cultured cells. When expressed in COS cells, the mutant proteins as well as the wild-type protein were localized predominantly in the endoplasmic reticulum and were sensitive to Endo-H treatment. NOV did not alter this localization or Endo-H sensitivity, suggesting that it acted in the endoplasmic reticulum. Profiling of β-alkyl-β-valienamines with various lengths of the acyl chain showed that β-dodecyl-β-valienamine was as effective as NOV. These results suggest a potential therapeutic value of NOV and related compounds for GD with a broad range of β-Glu mutations.Niemann-Pick disease type C (NPC) is a lipid storage disorder caused by mutations in NPC1 (NPC2) genes. We found that human NPC fibroblasts secrete several cytokines and contain increased levels of STATs. These cells also contained increased levels of TLR4. In the NPC model mouse brain, glial cells expressed TLR4 and IL-6, whereas both glial and neuronal cells expressed STATs. Genetic deletion of TLR4 in NPC model mice reduced IL-6 secretion but failed to alter STAT levels or glial cell activation in the brain. In contrast, genetic deletion of IL-6 normalized STAT levels and suppressed glial cell activation. These findings indicate that constitutive cytokine secretion leads to activation of STATs and that this secretion is partly caused by an endosomal accumulation of TLR4. These results also suggest that similar signaling events may underlie glial cell activation in the NPC brain