| First Author | Wu KC | Year | 2017 |
| Journal | Neurobiol Dis | Volume | 104 |
| Pages | 61-72 | PubMed ID | 28476637 |
| Mgi Jnum | J:259759 | Mgi Id | MGI:6141942 |
| Doi | 10.1016/j.nbd.2017.05.001 | Citation | Wu KC, et al. (2017) The critical role of Nramp1 in degrading alpha-synuclein oligomers in microglia under iron overload condition. Neurobiol Dis 104:61-72 |
| abstractText | Oligomeric alpha-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 alpha-synuclein. In this study, concomitant with the accumulation of iron and oligomeric alpha-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 alpha-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 alpha-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 alpha-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 alpha-synuclein under iron overload condition and may be implicated in the pathogenesis of PD. |
