The Role of the NADPH Oxidase NOX2 in Prion Pathogenesis
Silvia Sorce, Mario Nuvolone, Annika Keller, Jeppe Falsig, Ahmet Varol,
Petra Schwarz, Monika Bieri, Herbert Budka, Adriano Aguzzi mail
Published: December 11, 2014 •DOI: 10.1371/journal.ppat.1004531
Abstract
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.
Author Summary
The deposition of misfolded, aggregated prion protein in the brain causes
transmissible spongiform encephalopathies (TSE), a group of disorders including
Creutzfeldt–Jakob disease and mad cow disease. TSE are characterized by
neurodegeneration and progressive, lethal neurological dysfunction. Signs of
oxidative damage are found in TSE, implying excessive production of reactive
oxygen species (ROS), yet their source is unclear. Here, we analyzed the role of
the NADPH oxidase enzyme, NOX2, in prion pathogenesis. NOX2 is a membrane-bound
electrochemical pump that generates ROS. We found that NOX2 is upregulated in
the brains of patients with Creutzfeldt-Jakob disease and of prion-infected
mice. Interestingly, NOX2 ablation led to abrogation of ROS production in mice
inoculated with prions, and was associated with a milder clinical course of the
disease and increased life expectancy. We conclude that NOX2 is a relevant
contributor to the excessive production of ROS. This study spawns the
possibility that inhibiting NOX2 activation might help attenuate prion disease
progression – a legitimate and important goal even if there is little reason to
expect anti-NOX2 therapies to be curative.
snip...
Although NOX2 ablation does not ultimately prevent the development of prion
disease, the results presented above show that NOX2 is a relevant constituent of
the neurotoxic cascade in these diseases. Ablation or overexpression of
superoxide dismutase, SOD1, activity can decrease or increase prion incubation
time, respectively [7], [12]. Together with these previous findings, our data
support the crucial impact of superoxide production in prion diseases. Moreover,
they suggest that NOX2, expressed in microglial cells, is the major source of
this superoxide production. The use of antioxidants as possible therapeutic
approach for CNS diseases has been favored by promising results of rodent
studies; however, disappointing and incongruous outcomes have been observed in
clinical trials [50], [51]. Lack of specificity of antioxidant treatments could
be one of the reasons that explain such a failure in clinical translation.
Having identified NOX2 as a possible specific target may offer an opportunity to
reduce the occurrence of oxidative stress insults in CJD patients. In
particular, our data suggest that inhibition of NOX2 may attenuate, at least
temporarily, the neurological dysfunctions associated with prion disease,
thereby enhancing the quality of life – a legitimate and important goal even if
the overall life expectancy may not be dramatically improved. ...
snip...end
see full text above link at PLOS, and once again, many thanks to PLOS et
al, and Scientist, for open access...tss
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