Increased Ndfip1 in the substantia nigra of Parkinsonian brains is associated with elevated iron levels

Iron misregulation is a central component in the neuropathology of Parkinson's disease. The iron transport protein DMT1 is known to be increased in Parkinson's brains linking functional transport mechanisms with iron accumulation. The regulation of DMT1 is therefore critical to the managem...

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Published inPloS one Vol. 9; no. 1; p. e87119
Main Authors Howitt, Jason, Gysbers, Amanda M, Ayton, Scott, Carew-Jones, Francine, Putz, Ulrich, Finkelstein, David I, Halliday, Glenda M, Tan, Seong-Seng
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 24.01.2014
Public Library of Science (PLoS)
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Summary:Iron misregulation is a central component in the neuropathology of Parkinson's disease. The iron transport protein DMT1 is known to be increased in Parkinson's brains linking functional transport mechanisms with iron accumulation. The regulation of DMT1 is therefore critical to the management of iron uptake in the disease setting. We previously identified post-translational control of DMT1 levels through a ubiquitin-mediated pathway led by Ndfip1, an adaptor for Nedd4 family of E3 ligases. Here we show that loss of Ndfip1 from mouse dopaminergic neurons resulted in misregulation of DMT1 levels and increased susceptibility to iron induced death. We report that in human Parkinson's brains increased iron concentrations in the substantia nigra are associated with upregulated levels of Ndfip1 in dopaminergic neurons containing α-synuclein deposits. Additionally, Ndfip1 was also found to be misexpressed in astrocytes, a cell type normally devoid of this protein. We suggest that in Parkinson's disease, increased iron levels are associated with increased Ndfip1 expression for the regulation of DMT1, including abnormal Ndfip1 activation in non-neuronal cell types such as astrocytes.
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Conceived and designed the experiments: JH GH S-ST. Performed the experiments: JH AG SA FC-J UP. Analyzed the data: JH AG FC-J DF. Wrote the paper: JH GH S-ST.
Competing Interests: The authors declare that they have no conflict of interest. DF is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0087119