published: 25 March 2013
Biometals in rare neurodegenerative disorders of
Sarah J. Parker1, Jari Koistinaho1, Anthony R. White2and Katja M. Kanninen1,2*
1Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
2Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
Peter Crouch, University
of Melbourne, Australia
Paula I. Moreira, University
of Coimbra, Portugal
Junming Wang, University of
Mississippi Medical Center, USA
Katja M. Kanninen, Department of
Neurobiology, A.I. Virtanen Institute
for Molecular Sciences,
University of Eastern Finland,
Yliopistonranta 1, 70211 Kuopio,
Copper, iron, and zinc are just three of the main biometals critical for correct functioning of
the central nervous system (CNS). They have diverse roles in many functional processes
including but not limited to enzyme catalysis, protein stabilization, and energy production.
The range of metal concentrations within the body is tightly regulated and when the
balance is perturbed, debilitating effects ensue. Homeostasis of brain biometals is mainly
controlled by various metal transporters and metal sequestering proteins. The biological
roles of biometals are vastly reviewed in the literature with a large focus on the connection
to neurological conditions associated with ageing. Biometals are also implicated in a
variety of debilitating inherited childhood disorders, some of which arise soon following
birth or as the child progresses into early adulthood. This review acts to highlight what we
know about biometals in childhood neurological disorders such as Wilson’s disease (WD),
Menkes disease(MD), neuronal ceroid lipofuscinoses(NCLs), and neurodegeneration with
brain iron accumulation (NBIA). Also discussed are some of the animal models available
to determine the pathological mechanisms in these childhood disorders, which we hope
will aid in our understanding of the role of biometals in disease and in attaining possible
therapeutics in the future.
Keywords: metals, neurodegeneration, childhood, copper, iron, zinc
The significance of biometals for the correct functioning of the
human brain has long been discovered. The importance of met-
als such as iron, zinc, and copper results from the numerous roles
that they have, such as stabilization of proteins and transcription
factors, acting as co-factors for metallochaperones for cellular
transport and their role in enzyme catalysis (Markossian and
Kurganov, 2003; Butterworth, 2010). Deviations of metal home-
ostasis have been linked to neurodegenerative disorders such as
Alzheimer’s disease (AD), Parkinson’s disease, Amyotrophic lat-
eral sclerosis, and Huntington’s disease (HD) (Dexter et al., 1993;
Deibel et al., 1996; Jomova et al., 2010; Skjorringe et al., 2012). A
risk factor in the development of many of these disorders appears
to be an increase in age. Although the pathological characteristics
of the disease are in most cases well-understood, the exact causes
are often unknown.
Neurodegeneration is not restricted to an ageing popula-
tion. Several debilitating neurodegenerative disorders affecting
children have been identified. These include neurodegeneration
with brain iron accumulation (NBIA), ATPase pathologies such
as Wilson’s/Menkes disease and neuronal ceroid lipofuscinoses
(NCLs). These disorders share several pathological features with
more common neurodegenerative diseases, including protein
aggregation and oxidative stress. Aberrant biometal homeostasis
has also been identified in children suffering from these diseases
(Table 1). What is not clear is whether the distinct changes in
metal levels cause neurodegeneration or occur as a result of the
neurodegeneration. In some cases, the pathology associated with
childhood disorders is clearly evident and often fatal at an early
age. Changes in metal levels have also been identified in children
with Autism spectrum disorder (ASD) which affects the behav-
ior of children more so than hinder them physically. Dissecting
the roles that biometals haveinthese disordersis fundamental for
finding potential therapeutics to reduce or inhibit neuropatho-
logicalchanges associated withaltered metal homeostasis (Yasuda
et al., 2011).
Since biometal homeostasis plays a major role in neurodegen-
metals have on the developing brain. Multiple childhood disor-
ders arise from defects in the concentrations of metals within the
corrected or prevented to avoidor ameliorate disease. Whilemost
of the childhood disorders are inherited and disease progression
ular disease characteristics and metal alterations within the brain
and other tissues for the development of therapeutic treatments
to provide these children with a chance at life.
Wilson’s disease (WD) is an autosomal recessive disease affecting
coppermetabolism (Bearnand Kunkel, 1954). Copper is involved
in neurotransmitter synthesis, cellular respiration, scavenging of
toxic free-radicals, and has an important role in maintaining
homeostasis of other trace elements such as iron (Butterworth,
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March 2013 | Volume 5 | Article 14 | 1
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Conflict of Interest Statement: The
was conducted in the absence of any
commercial or financial relationships
that could be construed as a potential
conflict of interest.
Received: 25 January 2013; accepted: 05
March 2013; published online: 25 March
Citation: Parker SJ, Koistinaho J, White
AR and Kanninen KM (2013) Biometals
in rare neurodegenerative disorders of
childhood. Front. Aging Neurosci. 5:14.
Copyright © 2013 Parker, Koistinaho,
White and Kanninen. This is an open-
access article distributed under the terms
of the Creative Commons Attribution
License, which permits use, distribution
and reproduction in other forums, pro-
vided the original authors and source
are credited and subject to any copy-
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