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 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.
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
Jason
J
Howitt
Neuroscience Research Australia and the University of New South Wales, Sydney, Australia.
Amanda M
AM
Gysbers
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
Scott
S
Ayton
Neuroscience Research Australia and the University of New South Wales, Sydney, Australia.
Francine
F
Carew-Jones
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
Ulrich
U
Putz
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
David I
DI
Finkelstein
Neuroscience Research Australia and the University of New South Wales, Sydney, Australia.
Glenda M
GM
Halliday
Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
Seong-Seng
SS
Tan
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D017136:Ion Transport; D007501:Iron / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D002352:Carrier Proteins; C110547:DMRT1 protein; D008565:Membrane Proteins; C451223:NDFIP1 protein, human; D014157:Transcription Factors; D051844:alpha-Synuclein; D007501:Iron