PLoS Pathogens | |
The Role of the NADPH Oxidase NOX2 in Prion Pathogenesis | |
Herbert Budka1  Ahmet Varol1  Silvia Sorce1  Annika Keller1  Jeppe Falsig1  Adriano Aguzzi1  Mario Nuvolone1  Petra Schwarz1  Monika Bieri2  | |
[1] Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland;Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland | |
关键词: Prion diseases; Microglial cells; Animal prion diseases; Vacuoles; Brain diseases; Immunohistochemistry techniques; Oxidative stress; Veterinary diseases; | |
DOI : 10.1371/journal.ppat.1004531 | |
学科分类:生物科学(综合) | |
来源: Public Library of Science | |
【 摘 要 】
Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post-inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis.
【 授权许可】
CC BY
【 预 览 】
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