期刊
NEUROBIOLOGY OF AGING
卷 36, 期 2, 页码 1183-1193出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2014.10.021
关键词
Ndfip1; Divalent metal transporter 1; Iron; Parkinson's disease; 6-OHDA
资金
- National Program of Basic Research - Ministry of Science and Technology of China [2011CB504102]
- National Foundation of Natural Science of China [81430024, 81100955, 31371081, 31271131]
- Department of Science and Technology of Shandong Province [ZR2012HZ005]
- Excellent Innovative Team of Shandong Province
- Taishan Scholars Construction Project
- Shandong Provincial Education Department [J11LC05]
- Department of Health of Shandong [2011QZ006]
Elevated iron levels and increased expression of divalent metal transporter 1 (DMT1) in the substantia nigra of Parkinson's disease (PD) have been reported. Nedd4 family-interacting protein 1 (Ndfip1), an adaptor protein for the Nedd4 family of ubiquitin ligases, played an essential role in regulating DMT1 and iron homeostasis in human cortical neurons. In this study, we demonstrated that the expression of Ndfip1 decreased in 6-hydroxydopamine(6-OHDA)-induced PD rats and 6-OHDA-treated MES23.5 dopaminergic cells. Further study showed that the decrease of Ndfip1 occurred earlier than the increase of DMT1 with iron-responsive element (DMT1 + IRE) in 6-OHDA-treated MES23.5 cells, indicating that the decrease of Ndfip1 might be involved in the increase of DMT1 + IRE. In addition, we demonstrated that overexpression of Ndfip1 caused DMT1 + IRE downregulation, resulting in the decreased iron influx and iron-induced neurotoxicity. Although Ndfip1 knockdown led to decreased protein levels of DMT1 + IRE, partially aggravated iron-induced neurotoxicity. Further experiments showed that 6-OHDA-induced decrease in Ndfip1 levels might be related to proteasomal and lysosomal activations and oxidative stress caused by 6-OHDA. These data suggest that decreased Ndfip1 expression might contribute to the pathogenesis of 6-OHDA-induced iron accumulation and Ndfip1 could attenuate 6-OHDA-induced iron accumulation via regulating the degradation of DMT1. (C) 2015 Elsevier Inc. All rights reserved.
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