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

Jason Howitt; Amanda M Gysbers; Scott Ayton; Francine Carew-Jones; Ulrich Putz; David I Finkelstein; Glenda M Halliday; Seong-Seng Tan

doi:10.1371/journal.pone.0087119

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

PLoS One. 2014 Jan 24;9(1):e87119. doi: 10.1371/journal.pone.0087119. eCollection 2014.

Authors

Jason Howitt¹, Amanda M Gysbers², Scott Ayton¹, Francine Carew-Jones², Ulrich Putz¹, David I Finkelstein¹, Glenda M Halliday², Seong-Seng Tan¹

Affiliations

¹ Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
² Neuroscience Research Australia and the University of New South Wales, Sydney, Australia.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Animals
Astrocytes / drug effects
Astrocytes / metabolism*
Astrocytes / pathology
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Dopaminergic Neurons / drug effects
Dopaminergic Neurons / metabolism*
Dopaminergic Neurons / pathology
Embryo, Mammalian
Female
Gene Expression Regulation
Humans
Ion Transport
Iron / metabolism*
Iron / pharmacology
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Knockout
Parkinson Disease / genetics*
Parkinson Disease / metabolism
Parkinson Disease / pathology
Primary Cell Culture
Signal Transduction
Substantia Nigra / metabolism*
Substantia Nigra / pathology
Transcription Factors / genetics
Transcription Factors / metabolism*
alpha-Synuclein / genetics
alpha-Synuclein / metabolism

Substances

Carrier Proteins
DMRT1 protein
Membrane Proteins
NDFIP1 protein, human
Transcription Factors
alpha-Synuclein
Iron

Grants and funding

This work was supported by the National Health and Medical Research Council (NH&MRC) and the Victorian Government through the Operational Infrastructure Scheme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.