Hindawi Publishing Corporation
Oxidative Medicine and Cellular Longevity
Volume 2012, Article ID 128647, 8 pages
Ironand Neurodegeneration:From CellularHomeostasis
Regina AndradeMenezes, andClaudinaRodrigues-Pousada
Instituto de Tecnologia Qu´ ımica e Biol´ ogica, Universidade Nova de Lisboa, EAN, Avenida da Rep´ ublica, 2781-901 Oeiras, Portugal
Correspondence should be addressed to Claudina Rodrigues-Pousada, email@example.com
Received 10 February 2012; Revised 21 March 2012; Accepted 5 April 2012
Academic Editor: Marcos Dias Pereira
Copyright © 2012 Liliana Batista-Nascimento et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
Accumulation of iron (Fe) is often detected in the brains of people suffering from neurodegenerative diseases. High Fe
concentrations have been consistently observed in Parkinson’s, Alzheimer’s, and Huntington’s diseases; however, it is not clear
are associated with genetic factors that cause Fe misregulation. Consequently, excessive intracellular Fe increases oxidative stress,
which leads to neuronal dysfunction and death. The characterization of the mechanisms involved in the misregulation of Fe
in the brain is crucial to understand the pathology of the neurodegenerative disorders and develop new therapeutic strategies.
thus it could perhaps become a valuable tool also to study the metalloneurobiology.
Iron (Fe) is the most important element for almost all types
of cells, including brain cells. It is an essential cofactor for
many proteins involved in the normal function of neuronal
tissues, such as the non-heme Fe enzyme tyrosine hydrox-
ylase required for the synthesis of myelin and the neuro-
transmitters dopamine, norepinephrine, and serotonin .
In a normal brain, Fe appears widely distributed by region
and cell-type and it accumulates progressively during aging
and neurodegenerative processes . Fe is an originator of
reactive oxygen species (ROS). Ferric iron (Fe3+) can be
reduced to ferrous iron (Fe2+) by the superoxide radical
H2O2 generating the highly reactive hydroxyl free radical
(•OH) (Fe2++ H2O2 → Fe3++•OH + OH−, Fenton reac-
tion) . The combination of these reactions results in
the so-called Haber-Weiss reaction (O•
•OH + OH−), which together with dopamine oxidation can
trigger neurotoxicity . Therefore, the control of Fe home-
ostasis is essential to keep a healthy brain.
−) (Fe3++ O•
−→ Fe2++ O2). Fe2+can also react with
−+ H2O2 → O2+
1.1. Iron Homeostasis. In mammals, the regulatory mecha-
nism for Fe homeostasis is mediated by the iron-regulatory
proteins IRP1 and IRP2, which posttranscriptionally mod-
ulate the expression of specific mRNAs in response to
intracellular Fe [5, 6], mainly transferrin (Tf) and ferritin. Tf
is an Fe-binding blood plasma glycoprotein that controls the
of H and L subunits that assemble to form a hollow sphere
in which ferric iron (Fe3+) precipitates are sequestered .
The ferritin subunits have different functions. The H chains
are involved in the rapid oxidation of Fe2+to Fe3+, and the L
chains function in the nucleation of Fe3+within the protein
shell. While the L-rich ferritins are associated with iron
storage, the H-chain ferritins are associated with responses
to stress .
of TfR1. By binding to the IRE in the 5?UTR, of ferritin, IRPs
prevent translation, whereas by binding to IRE in the 3?UTR
of TfR1, the IRPs protect the transcript from degradation
. In Fe-replete cells, IRPs do not bind to IREs, and
2Oxidative Medicine and Cellular Longevity
ferritin and other transcripts are freely translated, whereas
TfR1 undergoes cleavage and subsequently degradation [6,
at the level of absorption, changes in gene expression in
response to Fe overload have been observed in a variety of
eukaryotes from yeast to mammals [12, 13].
Ferroportin (Fpn), the basolateral membrane Fe export-
er, is the only Fe exporter to date identified in mammals [14–
16]. Fpn mediates the release of the Fe in conjunction with
by Fpn to Fe3+before release into the extracellular medium
. Fpn expression has also been detected on the
blood-brain barrier (BBB) endothelial cells, neurons, oligo-
dendrocytes, astrocytes, the choroid plexus and ependymal
cells. Since Cp is essential for stabilization of Fpn, under
conditions of Cp deficiency or malfunction Fpn is not
expressed, which results in a decreased Fe efflux potentiating
plays a major role in maintaining Fe homeostasis in the brain
and in protecting it from Fe-mediated free radical injury.
is reduced to Fe2+that then is transported to the blood by
Fpn. In the blood, Cp oxidizes Fe2+to Fe3+and promotes its
binding to the serum iron carrier, Tf . In order to enter
BCSF (blood-cerebrospinal fluid) . The most common
pathway for Fe transference across the BBB is through the
TfRs expressed in the endothelial cells. The circulating Fe
bound to Tf is captured by TfR, entering the brain by
endocytosis and then is translocated across the endosomal
membrane, probably through the divalent metal transporter
1 (DMT1) . In addition to the Tf-TfR pathway, it has
been suggested that the lactoferrin receptor-lactoferrin (LfR-
Lf) pathway might also play a role in Fe transport across the
BBB. Fe2+in the cytoplasm can also be transported inside
the mitochondria by mitoferrin or participate in electron
exchange reactions [22, 23]. Figure 1 summarizes the brain
Fe uptake pathways.
Fe-related neurodegenerative disorders can result from
both iron accumulation in specific brain regions or defects
in its metabolism and/or homeostasis.
As the brain ages, Fe accumulates in regions that exhibit
pathologic characteristics of Alzheimer’s disease (AD) ,
Parkinson’s disease (PD) , or Huntington’s disease (HD)
[26, 27]. In younger individuals, the largest amounts of Fe
are in the oligodendrocytes whereas in older individuals
over 60 years old most of the Fe is found in the microglia
and astrocytes of the cortex, cerebellum, hippocampus, basal
ganglia, and amygdala . In these regions Fe is either
bound to neuromelanin, a dark brown pigment that accu-
mulates essentially iron, or to ferritin . Interestingly,
neurons express mostly H-ferritin, microglia express mostly
L-ferritin, and oligodendrocytes express similar amounts of
both subunits [29, 30]. Additionally neurons excrete the
nonrequired Fe through the carrier Fpn (Figure 1).
It has been widely accepted that abnormal high con-
centrations of Fe contribute to neurodegenerative processes;
however, a major question has not yet been answered. Is the
excessive Fe accumulation in the brain an initial event that
causes neurodegeneration or a consequence of the disease
Fe accumulation has been shown to lead to neuronal
death . Available Fe interacts with molecular oxygen and
generates reactive oxygen species (ROS) through Fenton and
Haber-Weiss reactions [32, 33], which leads to oxidative
stress. Mitochondrial dysfunction has also been raised as a
common cause for a number of neurodegenerative diseases.
formation , malfunction can result in a low Fe-S cluster
synthesis and consequent activation of DMT1 and decrease
of Fpn1, Fe accumulation, and oxidative stress . Oxidative
injury induces lipid peroxidation, nucleic acid modification,
of age-related neurodegeneration and is characterized by the
progressive loss of memory, task performance, speech, and
recognition of people and objects. AD is characterized by the
accumulation of aggregates of insoluble amyloid-β protein
itates/aggregates of hyperphosphorylated tau protein .
the amyloid senile plaques (SP) and neurofibrillary tangles
(NFTs) . The excessive Fe can lead to alterations in the
interaction between IRPs and their IREs  and disruption
studies have suggested that high Fe toxicity may be due to
the propensity of Fe2+to generate ROS , and postmortem
analysis of AD patients’ brains has revealed activation of
two enzymatic indicators of cellular oxidative stress: heme
oxygenase-1 (HO-1)  and NADPH oxidase . In addi-
tion, other evidence suggests that in AD the Fe metabolism
is disrupted. Tf is not found in the oligodendrocytes but
rather trapped within senile plaques and ferritin is expressed
within reactive microglial cells that are present both in and
around the senile plaques . A decade ago Rogers et al.
 provided another link between iron metabolism and
AD pathogenesis by describing the presence of an IRE in the
5?UTR of the amyloid precursor protein (APP) transcript.
APP 5?UTR is responsive to intracellular iron levels, which
regulate translation of APP holo-protein mRNA by a
mechanism similar to the translation of ferritin-L and -H
mRNAs via IREs in their 5?UTRs. Recently, Duce et al. 
have described that APP is a ferroxidase that couples with
Fpn to export Fe. In AD APP ferroxidase activity appears
inhibited, thereby causing neuronal Fe accumulation.
1.3. Parkinson’s Disease (PD). PD is a progressive disorder
that manifests as tremor at rest, bradykinesia, gait abnor-
malities, rigidity, postural dysfunction, and loss of balance
. It is the most prevalent neurodegenerative disorder
neurons  and the deposition of intracellular inclu-
sion bodies known as Lewy bodies. The principal protein
Oxidative Medicine and Cellular Longevity3
Figure 1: The brain iron homeostasis. Iron (Fe) binds to transferrin (Tf), enters the brain through the transferrin receptors (TfR) by
endocytosis, and translocates across the endosomal membrane through the divalent metal transporter 1 (DMT1). Lactoferrin receptors
and accumulates around the neuromelanin. Ferroportin (Fpn) transports Fe2+outside the neuron that is oxidized to Fe3+by ceruloplasmin
promoting its binding to Tf.
component of these bodies is α-synuclein (α-syn) that is
ubiquitously expressed in the brain .
Several studies have confirmed an increase of Fe in the
substantia nigra of most severe cases of PD [49–51]; however,
there are still some conflicting reports about the stage during
disease progression at which nigral Fe changes occur.
Fe levels increase in PD, possibly leading to nigrostriatal
dopamine neuron degeneration as a result of its ability to
produce ROS and cause lipid peroxidation [52, 53].
The elevated Fe content, besides contributing to the
increase of oxidative stress, also enhances α-syn aggregates
. It has been shown that α-syn harbors an IRE in its 5?-
UTR. Thus high intracellular Fe might also regulate α-syn
aggregation through the IRE/IRP system, therefore, causing
the death of dopaminergic neurons . As Fe deposits are
commonly found in the Lewy bodies, Fe might play a role on
the pathogenicity of α-syn in PD.
1.4. Huntington’s Disease (HD). HD is a neurodegenerative
disorder characterized by progressive motor, cognitive, and
psychiatric deterioration. Typically, onset of symptoms is
in middle-age (30 and 50 years old), but the disorder can
manifest at any time between infancy and elderliness. HD
is caused by a dominant glutamine expansion (CAG repeat
coding) within the N-terminal of the huntingtin protein that
initiates events leading to neuronal loss primarily within the
striatum and cerebral cortex. Full-length huntingtin is large
(∼350kD), but it is the smaller N-terminal fragments that
are the main mediators of disease progression . These
fragments have aberrant interactions with themselves and
other biomolecules that lead to the molecular hallmarks
of HD including aggregates, transcriptional repression ,
oxidative damage, and metabolic dysfunction .
For individuals with HD, increased Fe levels have pri-
marily been observed in the basal ganglia, namely, in the
striata and the globus pallidus . In addition, ferritin-Fe
levels are increased in striata of early clinical HD patients as
measured by magnetic resonance imaging (MRI) . Fe
levels increase early stage in HD and continue to increase
with age, which suggests that Fe may play a role in the pro-
this process are not yet understood. Although both AD and
PD are characterized by Fe accumulation, the Fe regulation
patterns seem to be different from HD . For instance,
Parkinson’s disease is characterized by Fe accumulation in
the substantia nigra, which has not been observed in HD.
It is possible that in HD Fe accumulation occurs because
after neuronal loss, cells with higher Fe content replace the
dead cells. Thus Fe accumulation in HD is most probably a
secondary effect of the disease .
1.5. Other Neurological Disorders. The accumulation of Fe
has also been implicated in a series of other neurological dis-
eases, such as Neuroferritinopathy, Hallervorden-Spatz syn-
drome, and Aceruloplasminemia that are characterized by
mutations in genes that encode for ferritin light polypeptide
(FTL), pantothenate kinase (PANK2), and ceruloplasmin,
Neuroferritinopathy is dominantly inherited and is a
midal features similar to HD and PD. It is caused by a single
adenine insertion at position 460-461 that is predicted to
change the C-terminal residues of the gene encoding L-chain
ferritin . Brain histochemistry of patients with neurofer-
ritinopathy showed abnormal aggregates of ferritin and Fe
and low serum ferritin concentrations. The C-terminus of
the aberrant L chain might interfere with the formation of
4Oxidative Medicine and Cellular Longevity
the hollow sphere allowing inappropriate release of Fe from
the loaded ferritin .
Another evidence for the involvement of Fe in neu-
rodegeneration is provided by the study of Hallervorden-
with brain-iron accumulation 1 (NBIA) or pantothenate-
kinase-2-associated neurodegeneration (PANK2) . HSS
is an autosomal recessive disorder characterized by dystonia,
pigmentary retinopathy in children and neuropsychiatric
defects in adults. The HSS patient’s MRI has a characteristic
pattern in the globus pallidus, known as “the eye of the
tiger” because of its appearance . Zhou et al. 
identified the genetic basis for this neurodegenerative disease
in which Fe accumulation is most dramatic by detecting
the underlying mutations in the gene that encodes for
pantothenate-kinase. This enzyme is essential for the coen-
zyme A biosynthesis , which in turn catalyzes the phos-
phorylation of pantothenate (vitamin B5), N-pantothenoyl-
cysteine, and pantetheine . The product of this reac-
tion, 4?-phosphopantothenate, is then converted to 4?-
phosphopanthetheine in a reaction that consumes cysteine.
HSS results from 4?-phosphopantothenate deficit, which is
caused by genetic defects in PANK2. Given that cysteine is
consumed in the conversion of 4?-phosphopantothenate, an
absence of functional PANK2 might explain the observed
accumulation of cysteine in the degenerating brain areas of
HSS patients. Consequently the cysteine Fe-chelating prop-
erties might account for the observed regional Fe accumu-
lation, and cysteine-bound Fe may promote Fe-dependent
oxidative damage in these regions . Even though PANK2
is not directly involved in Fe metabolism, its absence may
contribute for Fe accumulation in the brain, leading to
neuronal death via oxidative stress.
Finally, aceruloplasminemia, an autosomal recessive dis-
order caused by mutations in the ceruloplasmin gene, also
results in Fe overload in the brain characterized mainly by
retinal neurodegeneration . Cp is a multicopper fer-
roxidase responsible for the Fe homeostasis by promoting
Fe incorporation into Tf, therefore, playing a key role in
releasing Fe from the cells . Consequently, mutations in
the ceruloplasmin gene may cause Fe metabolism misregu-
lation in the brain. Due to the low release of cellular Fe and
the high nontransferrin-bound Fe uptake, the intracellular
Fe concentration becomes abnormally high. This induces
oxidative stress and formation of ROS triggering a cascade
of pathological events that lead to neuronal death.
1.6. Fe-Chelation Therapies. Oxidative stress, protein aggre-
gation, and active redox Fe have been considered promising
pharmacological targets for the treatment of AD and PD.
BBB permeable Fe chelators can be used as potential thera-
peutic agents in the treatment of neurodegenerative diseases.
A promising Fe chelator is desferrioxamine (Desferal), which
has been shown to prevent up to 60% of dopaminergic
neurons from death in a rat model of PD . The main
disadvantage of desferrioxamine is that it cannot cross the
BBB, due to its size and hydrophobicity . Clioquinol, a
small lipophilic Fe chelator that can cross the BBB, has also
proved to have beneficial effects in patients with AD .
However, clioquinol is not iron selective and has very toxic
effects. Aroylhydrazones are the new nontoxic lipophilic Fe
chelators that can form a neutral complex with Fe and
diffuse out of the membrane . Other important class
of compounds proposed for therapy is the polyphenols that
have antioxidant properties and can bind Fe . A major
limitation is their capacity to be absorbed at the gastroin-
testinal tract and subsequently be transported through the
The development of an effective non-toxic therapeutic
agent for such complex brain disorders still represents a
In the last decade, the budding yeast Saccharomyces cerevisiae
has been used as a model system to gain insights about the
mechanisms of neurodegenerative disorders such as Parkin-
son’s, Huntington’s, and Alzheimer’s . Yeast cells are
generally used to study key proteins involved in the etiology
and/or pathology of these diseases. When a yeast homologue
exists, the corresponding gene can be easily disrupted or
overexpressed to determine the loss or gain of function
phenotypes, respectively. When a yeast homologue is not
present, the human gene can be expressed in yeast and any
relevant phenotype that results from this expression can be
analyzed. The latter has been called humanized yeast models
. Despite their simplicity, yeast cells possess most of
the same basic cellular machinery as neurons in the brain,
including pathways required for protein homeostasis and
energy metabolism. Also their easy genetic manipulation
makes these cells an ideal tool for molecular biology.
humans . S. cerevisiae expresses three genetically distinct
transport systems for Fe, two reductive systems and one
nonreductive system. The reductive Fe uptake system con-
sists in a low-affinity pathway defined by Fet4, that can also
transport other metals and in a high-affinity pathway that is
mediated by a protein complex composed of a multicopper
ferroxidase Fet3, the mammalian Cp homologue, and a
permease Ftr1. The Fet3-Ftr1 complex is specific for Fe and
is regulated both transcriptionally and posttranscriptionally
by this metal [75–77]. The nonreductive Fe uptake system
is mediated by the ARN family (Arn1-4) of membrane
permeases that transport siderophore-Fe3+complexes [78,
79]. Additionally Harris et al.  showed for the first time
that Fet3 can functionally replace ceruloplasmin in restoring
Moreover, cells are able to spare Fe through the regula-
tion of Tis11 homologues and Cth1/2-mediated degradation
of mRNAs coding for Fe-binding proteins, thereby facilitat-
ing the utilization of limited cellular Fe levels [81, 82].
Since S. cerevisiae lacks the Fe storage protein, ferritin,
during Fe overload this is sequestered into the vacuole by
the Ccc1 transporter, which is under the control of the
Yap5 transcription factor . On the other hand, Fet5/Fth1
complex mobilizes Fe out of the vacuole for use during Fe
Oxidative Medicine and Cellular Longevity5
Given the similarities between yeast and mammals and
the availability of humanized S. cerevisiae strains, yeast
could potentially become an effective model to dissect the
molecular pathway associated with the misregulation of Fe
homeostasis in the neurodegenerative diseases.
lation in a neurodegenerative disease was first reported for
Friedreich’s ataxia (FRDA). FRDA is an autosomal recessive
mitochondrial disorder that causes progressive damage to
the nervous system, resulting in gait disturbance, speech
problems, heart disease, and diabetes. It is caused by GAA
triplet expansion in the first intron of the frataxin gene (FA)
A gene with high sequence similarity to FA was initially
identified in yeast, the yeast frataxin homologue, YFH1
 and later it was shown that the two proteins were both
located in the mitochondria. Moreover, human FA could
complement for the absence of the yeast yfh1 . However,
FA function was only discovered when Lodi and coworkers
 showed that the YFH1 knockout strain led to an
excessive Fe accumulation in the mitochondria resulting in
the generation of ROS and consequently oxidative damage.
The yeast frataxin homologue provided the evidence that
FRDA is indeed a mitochondrial disorder. The yeast model
and provided a tool for assaying therapeutic targets.
In this paper, we have summarized the role of Fe, a redox-
active transition metal, in neurodegenerative disorders.
Despite a considerable investigation already performed, it is
still not clear whether excessive Fe accumulation in the brain
is an initial event that causes neuronal death or is a conse-
quence of the disease process. The growing evidence suggests
causes, as found in patients with aceruloplasminemia, or
sporadic causes that can disrupt the normal mechanisms
of Fe transport into the brain. In addition, elevated Fe
levels generate ROS and increase the levels of oxidative
stress, which is considered one of the pathways leading to
neuronal death. A new study from Lei et al.  shows that
loss of Tau impairs the Fpn Fe export by preventing the
leading to Fe accumulation, which results in degeneration
of dopaminergic neurons in PD. These findings suggest the
involvement of a new mechanism associated with Tau’s role
in PD. However, the precise role of Fe transport proteins
in the brain is not completely understood, which impairs
the success of therapeutic strategies to prevent the damaging
effects of the Fe in the brain.
Finally, we believe that the use of the yeast neurodegen-
erative disease models might provide valuable insights into
key aspects of the Fe pathology in the brain and pave the way
towards the discovery of promising therapeutic targets.
This paper was supported by Grants from the Fundac ¸˜ ao para
a Ciˆ encia e a Tecnologia (FCT), no. SFRH/BD/39389/2007
to L. Batista-Nascimento, no. SFRH/BPD/35052/2007 to C.
Pimentel, no. SFRH/BPD/26506/2006 to R. A. Menezes
and no. PTDC/BIAMIC/108747/2008 and Pest-OE/EQB/
LA0004/2011 to C. Rodrigues-Pousada.
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