Open Access 01-12-2013 | Research
Analysis of inflammation-related nigral degeneration and locomotor function in DJ-1 −/− mice
Published in: Journal of Neuroinflammation | Issue 1/2013
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Background
Complex interactions involving genetic susceptibility and environmental
factors are thought to underlie the pathogenesis of Parkinson’s
disease (PD). Although the role of inflammatory processes in modulating risk
for development of PD has yet to be fully understood, prospective studies
suggest that chronic use of NSAIDs reduce the incidence of PD.
Loss-of-function mutations in the DJ-1 gene cause a rare form of
familial PD with an autosomal recessive pattern of inheritance; however,
DJ-1−/− mice do not display nigrostriatal pathway
degeneration, suggesting that additional factors such as inflammation may be
needed to induce neurodegeneration on the background of DJ-1 gene
mutations. Neuroinflammation causes oxidative stress and, based on evidence
that DJ-1 plays a protective role against oxidative stress, we investigated
whether DJ-1−/− mice display increased vulnerability to
inflammation-induced nigral degeneration.
Methods
We exposed adult wild-type and DJ-1−/− mice to repeated
intranasal administration of soluble TNF (inTNF) or repeated intraperitoneal
injections of low-dose lipopolysaccharide (LPS) or saline vehicle. We
measured locomotor performance using a variety of behavior tasks, striatal
dopamine (DA) content by HPLC, DA neuron (TH+ cells) and total neuron (NeuN+
cells) number in the substantia nigra pars compacta and ventral tegmental
area by unbiased stereology, number of Iba1-positive microglia, and mRNA
levels of inflammatory and oxidative stress genes by quantitative PCR in the
midbrain, cortex and isolated peritoneal macrophages of
DJ-1−/− and wild-type mice.
Results
We found that chronic LPS injections induced similar neuroinflammatory
responses in the midbrains of DJ-1−/− mice and
wild-type mice and neither group developed locomotor deficits or nigral
degeneration. inTNF administration did not appear to induce
neuroinflammatory responses in LPS-treated wild-type or
DJ-1−/− mice. The lack of vulnerability to
inflammation-induced nigral degeneration was not due to enhanced
anti-oxidant gene responses in the midbrains of DJ-1−/−
mice which, in fact, displayed a blunted response relative to that of
wild-type mice. Peripheral macrophages from wild-type and
DJ-1−/− mice displayed similar basal and
LPS-induced inflammatory and oxidative stress markers in vitro.
Conclusions
Our studies indicate that DJ-1−/− mice do not display
increased vulnerability to inflammation-related nigral degeneration in
contrast to what has been reported for
1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine. We conclude that either DJ-1
does not have a critical role in protecting DA neurons against
inflammation-induced oxidative stress and/or there is compensatory gene
expression in the midbrain of DJ-1−/− mice that renders
them resistant to the cytotoxic effects triggered by chronic peripheral
inflammation.