Inhibition of repulsive guidance molecule-a protects dopaminergic neurons in a mouse model of Parkinson’s disease
Autor: | Hitoshi Niwa, Yuki Fujita, Hideki Mochizuki, Wakana Oda, Kousuke Baba, Toshihide Yamashita |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
Male
Cancer Research Parkinson's disease Immunology Central nervous system Cell death in the nervous system Substantia nigra Article Cellular and Molecular Neuroscience chemistry.chemical_compound Mice medicine Animals lcsh:QH573-671 Microglia Tyrosine hydroxylase business.industry lcsh:Cytology MPTP Dopaminergic Neurons Parkinson Disease Cell Biology Repulsive guidance molecule A medicine.disease Cell biology Disease Models Animal medicine.anatomical_structure chemistry nervous system Axon guidance business |
Zdroj: | Cell Death and Disease, Vol 12, Iss 2, Pp 1-15 (2021) Cell Death & Disease |
ISSN: | 2041-4889 |
Popis: | Repulsive guidance molecule-a (RGMa), a glycosylphosphatidylinositol-anchored membrane protein, has diverse functions in axon guidance, cell patterning, and cell survival. Inhibition of RGMa attenuates pathological dysfunction in animal models of central nervous system (CNS) diseases including spinal cord injury, multiple sclerosis, and neuromyelitis optica. Here, we examined whether antibody-based inhibition of RGMa had therapeutic effects in a mouse model of Parkinson’s disease (PD). We treated mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and found increased RGMa expression in the substantia nigra (SN). Intraventricular, as well as intravenous, administration of anti-RGMa antibodies reduced the loss of tyrosine hydroxylase (TH)-positive neurons and accumulation of Iba1-positive microglia/macrophages in the SN of MPTP-treated mice. Selective expression of RGMa in TH-positive neurons in the SN-induced neuronal loss/degeneration and inflammation, resulting in a progressive movement disorder. The pathogenic effects of RGMa overexpression were attenuated by treatment with minocycline, which inhibits microglia and macrophage activation. Increased RGMa expression upregulated pro-inflammatory cytokine expression in microglia. Our observations suggest that the upregulation of RGMa is associated with the PD pathology; furthermore, inhibitory RGMa antibodies are a potential therapeutic option. |
Databáze: | OpenAIRE |
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