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

• Published in: PloS 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
• Language: English
• Published: United States Public Library of Science 24.01.2014; Public Library of Science (PLoS)
• Subjects: Aged; Aged, 80 and over; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Basal ganglia; Biology; Brain research; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell activation; Central nervous system diseases; Disease control; Divalent metal transporter-1; Dopamine; Dopamine receptors; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Embryo, Mammalian; Ethics; Experiments; Female; Gene Expression Regulation; Humans; Ion Transport; Iron; Iron - metabolism; Iron - pharmacology; Iron transport; Laboratory animals; Ligases; Male; Medicine; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mental health; Mice; Mice, Knockout; Movement disorders; Neurodegenerative diseases; Neurons; Neuropathology; Neurosciences; Neurotoxicity; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Parkinsons disease; Pathogenesis; Post-translation; Primary Cell Culture; Protein expression; Protein transport; Proteins; Signal Transduction; Studies; Substantia nigra; Substantia Nigra - metabolism; Substantia Nigra - pathology; Synuclein; Transcription Factors - genetics; Transcription Factors - metabolism; Transport; Ubiquitin; Ubiquitin-protein ligase; Australia
• DOI: 10.1371/journal.pone.0087119
• ISSN: 1932-6203

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.