Article

Neurotoxicity Research

, Volume 19, Issue 1, pp 63-72

Neuromelanin Activates Microglia and Induces Degeneration of Dopaminergic Neurons: Implications for Progression of Parkinson’s Disease

  • Wei ZhangAffiliated withDepartment of Neurology, Beijing Tiantan Hospital
  • , Kester PhillipsAffiliated withDepartment of Psychiatry, Neurology and Pharmacology, Columbia University
  • , Albert R. WielgusAffiliated withNeuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health
  • , Jie LiuAffiliated withInorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute, National Institute of Environmental Health Sciences/National Institutes of Health
  • , Alberto AlbertiniAffiliated withInstitute of Biomedical Technologies-Italian National Research Council
  • , Fabio A. ZuccaAffiliated withInstitute of Biomedical Technologies-Italian National Research Council
  • , Rudolph FaustAffiliated withDepartment of Psychiatry, Neurology and Pharmacology, Columbia University
  • , Steven Y. QianAffiliated withNeuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health
  • , David S. MillerAffiliated withNeuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health
    • , Colin F. ChignellAffiliated withNeuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health
    • , Belinda WilsonAffiliated withNeuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health
    • , Vernice Jackson-LewisAffiliated withDepartment of Neurology, Columbia University
    • , Serge PrzedborskiAffiliated withDepartment of Neurology, Pathology and Cell Biology, Columbia University
    • , Danielle JosetAffiliated withDepartment of Physiology and Cellular Biophysics, Columbia University
    • , John LoikeAffiliated withDepartment of Physiology and Cellular Biophysics, Columbia University
    • , Jau-Shyong HongAffiliated withNeuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health
    • , David SulzerAffiliated withDepartment of Psychiatry, Neurology and Pharmacology, Columbia University
    • , Luigi ZeccaAffiliated withInstitute of Biomedical Technologies-Italian National Research Council Email author 

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Abstract

In Parkinson’s disease (PD), there is a progressive loss of neuromelanin (NM)-containing dopamine neurons in substantia nigra (SN) which is associated with microgliosis and presence of extracellular NM. Herein, we have investigated the interplay between microglia and human NM on the degeneration of SN dopaminergic neurons. Although NM particles are phagocytized and degraded by microglia within minutes in vitro, extracellular NM particles induce microglial activation and ensuing production of superoxide, nitric oxide, hydrogen peroxide (H2O2), and pro-inflammatory factors. Furthermore, NM produces, in a microglia-depended manner, neurodegeneration in primary ventral midbrain cultures. Neurodegeneration was effectively attenuated with microglia derived from mice deficient in macrophage antigen complex-1, a microglial integrin receptor involved in the initiation of phagocytosis. Neuronal loss was also attenuated with microglia derived from mice deficient in phagocytic oxidase, a subunit of NADPH oxidase, that is responsible for superoxide and H2O2 production, or apocynin, an NADPH oxidase inhibitor. In vivo, NM injected into rat SN produces microgliosis and a loss of tyrosine hydroxylase neurons. Thus, these results show that extracellular NM can activate microglia, which in turn may induce dopaminergic neurodegeneration in PD. Our study may have far-reaching implications, both pathogenic and therapeutic.

Keywords

Substantia nigra Neuroinflammation Microglia Neurodegenerative diseases