Paraoxonase 2 (PON2) in the mouse central nervous system: A neuroprotective role?

Abstract

The aim of this study was to characterize the expression of paraoxonase 2 (PON2) in mouse brain and to assess its antioxidant properties. PON2 levels were highest in lung, intestine, heart and liver, and lower in brain; in all tissues, PON2 expression was higher in female than in male mice. PON2 knockout [PON2-/-] mice did not express any PON2, as expected. In brain, the highest levels of PON2 were found in the substantia nigra, the nucleus accumbens and the striatum, with lower levels in the cerebral cortex, hippocampus, cerebellum and brainstem. A similar regional distribution of PON2 activity (measured by dihydrocoumarin hydrolysis) was also found. PON3 was not detected in any brain area, while PON1 was expressed at very low levels, and did not show any regional difference. PON2 levels were higher in astrocytes than in neurons isolated from all brain regions, and were highest in cells from the striatum. PON2 activity and mRNA levels followed a similar pattern. Brain PON2 levels were highest around birth, and gradually declined. Subcellular distribution experiments indicated that PON2 is primarily expressed in microsomes and in mitochondria. The toxicity in neurons and astrocytes of agents known to cause oxidative stress (DMNQ and H2O2) was higher in cells from PON2-/- mice than in the same cells from wild-type mice, despite similar glutathione levels. These results indicate that PON2 is expressed in brain, and that higher levels are found in dopaminergic regions such as the striatum, suggesting that this enzyme may provide protection against oxidative stress-mediated neurotoxicity.

Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms

“…Protein was subjected to gel electrophoresis and transferred to polyvinylidene difluoride (PVDF) membranes and probed for PON2 (1:1000, at 4°C for two nights) and β-actin (1:1,000 for 1 hour at RT). These dilutions were optimized based on our prior work on PON2 protein expression in other cell types (Giordano et al 2011; 2013). Membranes were incubated in secondary antibodies tagged with horseradish peroxidase (rabbit anti- HRP, 1:1000 for 1 hour, RT) and developed.…”

The neuroprotective effect of lovastatin on MPP + -induced neurotoxicity is not mediated by PON2

“…As the expression 243 of PON2 is higher in the brain as compared with the other 244 paraoxonases (PON1 and PON3). A greater participation of PON2 in 245 the regulation of oxidative stress associated to various pathologies 246 would be expected (Giordano et al, 2011). However, the adminis-247 tration of MPP + in this study did not affect the PON2 activity levels.…”

Genetics of Amyotrophic Lateral Sclerosis

“…Thus, mutations in the PON genes could affect PON activity and thereby contribute to ALS pathogenesis. Toxicity in neurons caused by oxidative stress was higher in cells from PON2 knockout mice than in wild-type mice, suggesting that PON2 has a protective effect against neurotoxicity caused by oxidative stress (Giordano et al, 2011).…”

“…PON1 and PON3 are primarily expressed in liver where they are associated with high-density lipoproteins, whereas PON2 is ubiquitously expressed (Costa et al, 2005;Draganov et al, 2000;Ng et al, 2002). Both PON1 and PON2 expression has been shown in mouse brain (Giordano et al, 2011). All PON proteins are able to hydrolyze lactones and PON1 is able to detoxify organophosphate pesticides and neurotoxins.…”