Chemistry Reference
In-Depth Information
of 4-HNE and other
-unsaturated aldehydes serves as a site for Michael addition with the sulfur atom of
cysteine, the imidazole nitrogen of histidine, and, to a lesser extent, the amine nitrogen of lysine. After forming
Michael adducts, the aldehyde moiety may in some cases undergo Schiff base formation with amines of adjacent
lysines, producing intra- and/or inter-molecular cross-linking. Recent studies have suggested that such protein
carbonylation from lipid-derived aldehydes is more prevalent than that formed via direct amino acid side chain
oxidation.
Peroxynitrite is able to oxidise methionine residues and to nitrate tyrosine residues in proteins. Nitration of
tyrosine residues may contribute significantly to peroxynitrite toxicity, since nitration will prevent the phos-
phorylation or nucleotidylation of key tyrosine residues in enzymes which are regulated by phosphorylation/
adenylation, thereby seriously compromising one of the most important mechanisms of cellular regulation and
signal transduction.
ROS can also readily attack DNA, generating a variety of DNA lesions, such as oxidised bases, abasic sites,
and single- and double-strand breaks. If not properly removed, DNA damage can be potentially dangerous, leading
to mutagenesis and/or cell death, especially in the case of lesions that block the progression of DNA/RNA
polymerases.
a
,
b
NEURODEGENERATIVE DISEASES ASSOCIATED WITH METALS
1.
Parkinson's Disease (PD)
PD is the second most common neurodegenerative disease after AD affecting about 1% of the population older
than 60. Unlike AD, which affects memory and behaviour centres in the brain, PD is characterised by progressive
loss of control over voluntary movement. The characteristic symptoms (bradykinesia, rigidity, tremor, and loss of
balance) arise from the progressive loss of dopaminergic neurons (neurons which synthesise and release dopa-
mine) in the substantia nigra pars compacta (SNPC), located in the mid-brain. In PD, there is a two fold increase in
the iron content of the substantia nigra and the lateral globus pallidus. This is in marked contrast to other iron
storage diseases, like untreated genetic haemochromatosis, and thalassaemia patients, where 10- to 20-fold iron
increases in iron stores must be attained before clinical abnormalities occur. The etiology of such iron excesses are
unknown although it has been suggested that changes in iron release mechanisms across the BBB, or dysregulation
of iron transport across the membranes of specific brain regions may be involved. A second characteristic hallmark
of PD is the presence, within dopaminergic neurons, axons, and synapses of the substantia nigra, of intracellular,
eosinophilic proteinaceous aggregates called Lewy bodies, which are composed mostly of aggregates of ubiq-
uinated
a
-synuclein, but also contain, tyrosine hydroxylase and IRP 2. There are increased levels of iron in both
Lewy bodies within cytosolic compartments as well as in dopaminergic neurons of the substantia nigra in PD
patients which will cause oxidative damage.
Despite the increased brain iron content in PD, there is no corresponding upregulation of ferritin expression. As
we saw earlier, iron regulatory proteins, IRP-1 and IRP-2, act as iron sensors and regulate ferritin synthesis
(Chapter 7). IRP2 seems to play the predominant role in post-transcriptional regulation of iron metabolism in
brain. Changes in ubiquination appear to be an important facet of Parkinson's disease; since the degradation of
IRP-2 requires its ubiquitination and proteasomal degradation, this may be an explanation for the failure to
upregulate ferritin synthesis (which would require the inactivation of IRP2).
Genetically engineered mice, which lack IRP-2 but have the normal complement of IRP-1, develop adult onset
neurodegenerative disease associated with inappropriately high expression of ferritin in degenerating neurons.
Mice that are homozygous for a targeted deletion of IRP-2 and heterozygous for a targeted deletion of IRP-1
develop severe neurodegeneration with severe axonopathy, and increased levels of ferric iron and ferritin
expression, accompanied by degeneration of neuronal cell bodies in the substantia nigra.
The role of iron in PD is outlined in
Figure 21.6
. In the brain interstitial fluid, iron is transported bound to
transferrin (Tf) which is absorbed by neuronal cells via transferrin receptor (TfR1)-mediated endocytosis. Iron
