Neuroinflammation and α-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson's disease.
BACKGROUND
Mechanisms whereby gene-environment interactions mediate chronic, progressive neurodegenerative processes in Parkinson's disease (PD)-the second most common neurodegenerative disease-remain elusive.


OBJECTIVE
We created a two-hit [neuroinflammation and mutant α-synuclein (α-syn) overexpression] animal model to investigate mechanisms through which mutant α-syn and inflammation work in concert to mediate chronic PD neurodegeneration.


METHODS
We used an intraperitoneal injection of the inflammogen lipopolysaccharide (LPS; 3 × 106 EU/kg) to initiate systemic and brain inflammation in wild-type (WT) mice and transgenic (Tg) mice overexpressing human A53T mutant α-syn. We then evaluated nigral dopaminergic neurodegeneration, α-syn pathology, and neuroinflammation.


RESULTS
After LPS injection, both WT and Tg mice initially displayed indistinguishable acute neuroinflammation; however, only Tg mice developed persistent neuroinflammation, chronic progressive degeneration of the nigrostriatal dopamine pathway, accumulation of aggregated, nitrated α-syn, and formation of Lewy body-like inclusions in nigral neurons. Further mechanistic studies indicated that 4-week infusion of two inhibitors of inducible nitric oxide synthase and NADPH oxidase, major free radical-generating enzymes in activated microglia, blocked nigral α-syn pathology and neurodegeneration in LPS-injected Tg mice.


CONCLUSIONS
Microglia-derived oxidative stress bridged neuroinflammation and α-syn pathogenic alteration in mediating chronic PD progression. Our two-hit animal model involving both a genetic lesion and an environmental trigger reproduced key features of PD and demonstrated synergistic effects of genetic predisposition and environmental exposures in the development of PD. The chronic progressive nature of dopaminergic neurodegeneration, which is absent in most existing PD models, makes this new model invaluable for the study of mechanisms of PD progression.
Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA. gao2@niehs.nih.gov
Hui-Ming
HM
Gao
Feng
F
Zhang
Hui
H
Zhou
Wayneho
W
Kam
Belinda
B
Wilson
Jau-Shyong
JS
Hong
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001596:Benzylamines / Q000494:pharmacology; D004195:Disease Models, Animal; D007274:Injections, Intraperitoneal; D016631:Lewy Bodies / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D009861:Onium Compounds / Q000494:pharmacology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D013378:Substantia Nigra / Q000276:immunology / Q000473:pathology*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D000578:Amidines; D001596:Benzylamines; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009861:Onium Compounds; D051844:alpha-Synuclein; C007517:diphenyleneiodonium; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases
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