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Cologna S.M.,Program in Developmental Endocrinology and Genetics | Cluzeau C.V.M.,Program in Developmental Endocrinology and Genetics | Yanjanin N.M.,Program in Developmental Endocrinology and Genetics | Blank P.S.,Program in Physical Biology | And 6 more authors.
Journal of Inherited Metabolic Disease | Year: 2014

Niemann-Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post-mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C-X-C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL-3, IL-10 and IL-13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials. © 2013 Springer-Verlag Berlin Heidelberg (outside the USA).

Sik Jun H.,Program in Developmental Endocrinology and Genetics | Mok Lee Y.,Program in Developmental Endocrinology and Genetics | Duk Song K.,U.S. National Institutes of Health | Mansfield B.C.,Program in Developmental Endocrinology and Genetics | Chou J.Y.,Program in Developmental Endocrinology and Genetics
Blood | Year: 2011

G6PC3 (or glucose-6-phosphatase-β) deficiency underlies a congenital neutropenia syndrome in which neutrophils exhibit enhanced endoplasmic reticulum (ER) stress,increased apoptosis, impaired energy homeostasis,and impaired functionality. Here we show that murine G6pc3 -/- neutrophils undergoing ER stress activate protein kinase-like ER kinase and phosphatidylinositol 3,4,5-trisphosphate/Akt signaling pathways,and that neutrophil apoptosis is mediated in part by the intrinsic mitochondrial pathway. In G6PC3-deficient patients, granulocyte colony-stimulating factor (G-CSF) improves neutropenia, but its impact on neutrophil apoptosis and dysfunction is unknown. We now show that G-CSF delays neutrophil apoptosis in vitro by modulating apoptotic mediators. However,G6pc3 -/- neutrophils in culture exhibit accelerated apoptosis compared with wild-type neutrophils both in the presence or absence of G-CSF. Limiting glucose(0.6mM) accelerates apoptosis but is more pronounced for wild-type neutrophils,leading to similar survival profiles for both neutrophil populations. In vivo G-CSF therapy completely corrects neutropenia and normalizes levels of p-Akt, phosphatidylinositol 3,4,5-trisphosphate,and active caspase-3. Neutrophils from in vivo G-CSF-treated G6pc3 -/- mice exhibit increased glucose uptake and elevated intracellular levels of G6P, lactate,and adenosine-5-triphosphate, leading to improved functionality. Together,the results strongly suggest that G-CSF improves G6pc3 -/- neutrophil survival by modulating apoptotic mediators and rectifies function by enhancing energy homeostasis. © 2011 by The American Society of Hematology.

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