Iron mediates neuritic tree collapse in mesencephalic neurons treated with 1-methyl-4-phenylpyridinium (MPP+)
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Gómez, Francisco
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Iron mediates neuritic tree collapse in mesencephalic neurons treated with 1-methyl-4-phenylpyridinium (MPP+)
Abstract
Studies in post-mortem tissues of patients with
Parkinson’s disease (PD) and in mice treated with 6-hydroxydopamine
have shown a decrease in the length of
axon and dendrites of striatal neurons. However, the etiology
of the morphological changes and their relationship
to inhibition of mitochondrial complex I and the cellular
levels of iron and glutathione (GSH) have not been
described. In this study, we characterized the effect of
MPP?, an inhibitor of mitochondria complex I, on the
integrity of the neuritic tree of midbrain dopaminergic
neurons, and determined the influence of iron and cellular
levels of GSH on this degeneration. Sub-maximal concentrations
of MPP? induced a drastic dose-dependent
reduction of neurites, without modification of the soma or
apparent cell death. Concurrent treatment with MPP? and
non-toxic concentrations of iron accelerated the process of
degeneration, whereas neurons grown on a medium low in
iron showed enhanced resistance to MPP? treatment.
MPP?-induced neurite shortening depended on the redox
state of neurons. Pre-treatment with the general antioxidant
N-acetyl cysteine protected neurons from degeneration.
Treatment with sub-maximal concentrations of the inhibitor
of GSH synthesis buthionine sulfoximine (BSO), in
conjunction with iron and MPP?, produced massive cell
death, whereas treatment with BSO plus MPP? under low iron conditions did not damage neurons. These results
suggest that under conditions of inhibition of mitochondrial
complex I caused by MPP?, the accumulation of iron and
the concurrent decrease in GSH results in the loss of the
dendritic tree prior to cell death, of dopaminergic neurons
in PD.
General note
Artículo de publicación ISI
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This work was financed by Grant 1100599 from
Fondo Nacional de Ciencia y Tecnologı´a Chile, (FONDECYT) and
by project ICM-P05-001-F from the Millennium Scientific Initiative,
Ministerio de Planificacio´n Nacional (MIDEPLAN).
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J Neural Transm (2011) 118 : 421–431
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