The critical role of Nramp1 in degrading α-synuclein oligomers in microglia under iron overload condition
Journal
Neurobiology of Disease
Journal Volume
104
Pages
61-72
Date Issued
2017
Author(s)
Abstract
Oligomeric α-synuclein is a key mediator in the pathogenesis of Parkinson's disease (PD) and is mainly cleared by autophagy-lysosomal pathway, whose dysfunction results in the accumulation and cell-to-cell transmission of α-synuclein. In this study, concomitant with the accumulation of iron and oligomeric α-synuclein, higher expression of a lysosomal iron transporter, natural resistance-associated macrophage protein-1 (Nramp1), was observed in microglia in post-mortem striatum of sporadic PD patients. Using Nramp1-deficient macrophage (RAW264.7) and microglial (BV-2) cells as in-vitro models, iron exposure significantly reduced the degradation rate of the administered human α-synuclein oligomers, which can be restored by the expression of the wild-type, but not mutant (D543N), Nramp1. Likewise, under iron overload condition, mice with functional Nramp1 (DBA/2 and C57BL/6 congenic mice carrying functional Nramp1) had a better ability to degrade infused human α-synuclein oligomers than mice with nonfunctional Nramp1 (C57BL/6) in the brain and microglia. The interplay between iron and Nramp1 exhibited parallel effects on the clearance of α-synuclein and the activity of lysosomal cathepsin D in vitro and in vivo. Collectively, these findings suggest that the function of Nramp1 contributes to microglial degradation of oligomeric α-synuclein under iron overload condition and may be implicated in the pathogenesis of PD. ? 2017 Elsevier Inc.
SDGs
Other Subjects
alpha synuclein; cathepsin D; natural resistance associated macrophage protein 1; oligomer; AIF1 protein, human; alpha synuclein; ammonium ferric sulfate; cathepsin D; cation transport protein; DNA binding protein; ferric ion; glial fibrillary acidic protein; lysosome associated membrane protein 1; natural resistance-associated macrophage protein 1; TUBB3 protein, human; tubulin; animal cell; animal experiment; animal tissue; Article; brain tissue; C57BL 6 mouse; controlled study; corpus striatum; exposure; extraction; genetic transfection; human; human cell; human tissue; immunofluorescence; immunohistochemistry; in vitro study; in vivo study; iron overload; male; microglia; mouse; mutant; nonhuman; Parkinson disease; pathogenesis; priority journal; protein degradation; protein expression; RAW 264.7 cell line; Western blotting; wild type; aged; analysis of variance; animal; C57BL mouse; case control study; drug effects; female; genetics; metabolism; microglia; Parkinson disease; pathology; site directed mutagenesis; transformed cell line; transgenic mouse; very elderly; Aged; Aged, 80 and over; alpha-Synuclein; Analysis of Variance; Animals; Case-Control Studies; Cathepsin D; Cation Transport Proteins; Cell Line, Transformed; Corpus Striatum; DNA-Binding Proteins; Female; Ferric Compounds; Glial Fibrillary Acidic Protein; Humans; Lysosomal-Associated Membrane Protein 1; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Mutagenesis, Site-Directed; Parkinson Disease; Transfection; Tubulin
Publisher
Academic Press Inc.
Type
journal article