Browsing by Author "Mosqueira Montero, Matías José"

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    Lack of Activation of the Unfolded Protein Response in Mouse and Cellular Models of Niemann-Pick Type C Disease
    (2011) Klein Posternack, Andrés David; Mosqueira Montero, Matías José; Martínez, Gabriela; Robledo Plaza, Fermín Alberto; González Bustos, Marcela Paz; Caballero, Benjamín; Cancino Lobos, Gonzalo; Álvarez Rojas, Alejandra Beatriz; Hetz, Claudio; Zanlungo Matsuhiro, Silvana
    Background: Niemann-Pick type C (NPC) disease is a fatal lysosomal storage disease related to progressive neurode-generation secondary to abnormal intracellular accumulation of cholesterol. Signs of endoplasmic reticulum (ER) stress have been reported in other lipidoses. Adaptation to ER stress is mediated by the unfolded protein response (UPR), an integrated signal transduction pathway that attenuates stress or triggers apoptosis of irreversibly damaged cells. Objective: To investigate the possible engagement of ER stress responses in NPC models. Methods: We used NPC1 deficient mice and an NPC cell-based model by knocking down the expression of NPC1 to measure several UPR markers through different approaches. Results: Despite expectations that the UPR will be activated in NPC, our results indicate a lack of ER stress reactions in the cerebellum of symptomatic mice. Similarly, knocking down NPC1 in Neuro2a cells leads to clear cholesterol accumulation without evidence of UPR activation. Conclusion: Our results suggest that cholesterol overload and neuronal dysfunction in NPC is not associated with ER stress, which contrasts with recent reports suggesting the activation of the UPR in other lysosomal storage diseases. Copyright (c) 2010 S. Karger AG, Basel
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    Npc1 deficiency in the C57BL/6J genetic background enhances Niemann–Pick disease type C spleen pathology
    (2011) Parra Cares, Julio Alejandro; Klein, Andres D.; Castro, Juan Francisco; Morales France, María Gabriela; Mosqueira Montero, Matías José; Valencia Araya, Ilse; Cortés Mora, Víctor Antonio; Rigotti Rivera, Attilio; Zanlungo Matsuhiro, Silvana
    Niemann–Pick type C (NPC) disease is an autosomal recessive neurovisceral lipid storage disorder. The affected genes are NPC1 and NPC2. Mutations in either gene lead to intracellular cholesterol accumulation. There are three forms of the disease, which are categorized based on the onset and severity of the disease: the infantile form, in which the liver and spleen are severely affected, the juvenile form, in which the liver and brain are affected, and the adult form, which affects the brain. In mice, a spontaneous mutation in the Npc1 gene originated in the BALB/c inbred strain mimics the juvenile form of the disease. To study the influence of genetic background on the expression of NPC disease in mice, we transferred the Npc1 mutation from the BALB/c to C57BL/6J inbred background. We found that C57BL/6J-Npc1−/− mice present with a much more aggressive form of the disease, including a shorter lifespan than BALB/c-Npc1−/− mice. Surprisingly, there was no difference in the amount of cholesterol in the brains of Npc1−/− mice of either mouse strain. However, Npc1−/− mice with the C57BL/6J genetic background showed striking spleen damage with a marked buildup of cholesterol and phospholipids at an early age, which correlated with large foamy cell clusters. In addition, C57BL/6J Npc1−/− mice presented red cell abnormalities and abundant ghost erythrocytes that correlated with a lower hemoglobin concentration. We also found abnormalities in white cells, such as cytoplasmic granulation and neutrophil hypersegmentation that included lymphopenia and atypias. In conclusion, Npc1 deficiency in the C57BL6/J background is associated with spleen, erythrocyte, and immune system abnormalities that lead to a reduced lifespan.