Down-regulation of natural resistance-associated macrophage protein-1 (Nramp1) is associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP + )-induced α-synuclein accumulation and neurotoxicity
Journal
Neuropathology and Applied Neurobiology
Journal Volume
45
Journal Issue
2
Pages
157-173
Date Issued
2019
Author(s)
Abstract
Aims: The accumulation of α-synuclein is a hallmark in the pathogenesis of Parkinson′s disease (PD). Natural resistance-associated macrophage protein-1 (Nramp1) was previously shown to contribute to the degradation of extracellular α-synuclein in microglia under conditions of iron overload. This study was aimed at investigating the role of Nramp1 in α-synuclein pathology in the neurone under 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP+) treatment. Methods: The expression of Nramp1 and pathological features (including iron and α-synuclein accumulation) were examined in the dopaminergic neurones of humans (with and without PD) and of mice [with and without receiving chronic MPTP intoxication]. The effects of Nramp1 expression on low-dose MPP+-induced α-synuclein expression and neurotoxicity were determined in human dopaminergic neuroblastoma SH-SY5Y cells. Results: Similar to the findings in the substantia nigra of human PD, lower expression of Nramp1 but higher levels of iron and α-synuclein were identified in the dopaminergic neurones of mice receiving chronic MPTP intoxication, compared to controls. In parallel to the loss of dopaminergic neurones, the numbers of glial fibrillary acidic protein- and ionized calcium-binding adapter molecule-1-positive cells were significantly increased in the substantia nigra of MPTP-treated mice. Likewise, in human neuroblastoma SH-SY5Y cells exposed to low-dose MPP+, Nramp1 expression and cathepsin D activity were decreased, along with an increase in α-synuclein protein expression and aggregation. Overexpression of functional Nramp1 restored cathepsin D activity and attenuated α-synuclein up-regulation and neuronal cell death caused by MPP+ treatment. Conclusions: These data suggest that the neuronal expression of Nramp1 is important for protecting against the development of MPTP/MPP+-induced α-synuclein pathology and neurotoxicity. ? 2018 British Neuropathological Society
SDGs
Other Subjects
1 methyl 4 phenylpyridinium; 1,2,3,6 tetrahydro 1 methyl 4 phenylpyridine; alpha synuclein; calcium binding protein; cathepsin D; glial fibrillary acidic protein; ionized calcium binding adapter molecule 1; natural resistance associated macrophage protein 1; neuromelanin; unclassified drug; 1,2,3,6 tetrahydro 1 methyl 4 phenylpyridine; alpha synuclein; cation transport protein; glial fibrillary acidic protein; natural resistance-associated macrophage protein 1; aged; animal cell; animal experiment; animal model; Article; brain tissue; controlled study; dopaminergic nerve cell; down regulation; female; gene overexpression; human; human cell; human tissue; in vitro study; in vivo study; male; microglia; molecular pathology; mouse; MPTP-induced neurotoxicity; nerve cell necrosis; neuropathology; nonhuman; Parkinson disease; priority journal; protein aggregation; protein expression; protein function; SH-SY5Y cell line; substantia nigra; upregulation; very elderly; animal; drug effect; metabolism; Parkinson disease; pathology; tumor cell line; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Aged; Aged, 80 and over; alpha-Synuclein; Animals; Cation Transport Proteins; Cell Line, Tumor; Dopaminergic Neurons; Female; Glial Fibrillary Acidic Protein; Humans; Male; Mice; Microglia; Parkinson Disease; Substantia Nigra
Publisher
Blackwell Publishing Ltd
Type
journal article