Neuroinflammation and α-Synuclein Dysfunction Potentiate Each Other, Driving Chronic Progression of Neurodegeneration in a Mouse Model of Parkinson's Disease

• Published in: Environmental health perspectives Vol. 119; no. 6; pp. 807 - 814
• Main Authors: Gao, Hui-Ming, Zhang, Feng, Zhou, Hui, Kam, Wayneho, Wilson, Belinda, Hong, Jau-Shyong
• Format: Journal Article
• Language: English
• Published: Research Triangle Park, NC National Institute of Environmental Health Sciences 01.06.2011; US Department of Health and Human Services
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Amidines - pharmacology; Animal models; Animals; Animals, Genetically Modified; Antibodies; Benzylamines - pharmacology; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease models; Disease Models, Animal; Environment. Living conditions; Environmental health; Inflammation; Injections, Intraperitoneal; Lewy Bodies - pathology; Lipopolysaccharides - immunology; Lipopolysaccharides - pharmacology; Medical sciences; Mice; Microglia; NADPH Oxidases - antagonists & inhibitors; Nerve Degeneration - chemically induced; Nerve Degeneration - immunology; Nerve Degeneration - pathology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurodegenerative Diseases - chemically induced; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - immunology; Neurodegenerative Diseases - pathology; Neurology; Neurons; Nitric Oxide Synthase Type II - antagonists & inhibitors; Onium Compounds - pharmacology; Oxidases; Oxidative Stress; Parkinson disease; Parkinson Disease - genetics; Parkinson Disease - immunology; Parkinson Disease - pathology; Pathology; Public health. Hygiene; Public health. Hygiene-occupational medicine; Substantia Nigra - immunology; Substantia Nigra - pathology; Toxicology; NADPH; Animal model; Oxidative stress; Prognosis; Parkinson's disease; Oxidase; Parkinson disease; neurodegeneration; Health and environment; NADPH oxidase; Evolution; iNOS; Degenerative disease; α-synuclein; Nervous system diseases; gene―environment interaction; Enzyme; Vehicle driving; Rodentia; Inflammation; Nitric-oxide synthase; Cerebral disorder; Microglia; Vertebrata; Chronic; Mammalia; Genotype environment interaction; Mouse; Dysfunction; Central nervous system disease; Oxidoreductases; Extrapyramidal syndrome
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.1003013

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.