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Age-related Neurodegenerative Disease
Figure 1: GSTZ1 Function within the Phenylalanine–Tyrosine
supported the hypothesis that dopamine disposal pathways influence
Catabolic Pathway
cognitive ability in older adults. It is plausible that the ageing brain is
more vulnerable to increased levels of auto-oxidised products of
dopamine than it is in childhood. This would be consistent with the
Phenylalanine
observation that Parkinson’s disease incidence increases with age.
GSTZ1 and Parkinson’s Disease and Environmental Toxins
Tyrosine
Herbicides such as paraquat are implicated as environmental risk factors
for Parkinson’s disease. Their effect can be attenuated experimentally by
protecting oxidative stress pathways.
24
The glutathione redox cycle is
affected by paraquat, with a shift towards the oxidised state,
25
p-OH-phenylpyruvic Homogentistic
acid acid accompanied by decreased levels of GSTs. In particular, GSTP1 is
associated with Parkinson’s disease in people exposed to pesticides, but
no association has been identified for GSTZ1 so far.
26
The role of GSTZ1 in
Maleylacetoacetate
the oxygenation of DCA has already been mentioned. However,
administration of DCA itself substantially reduces GSTZ1 activity in animal
models.
27
This observation leads to the possibility that, in humans, chronic
GSTZ1
Succinoacetoacetate
exposure to chlorinated water will reduce GSTZ1 activity and consequently
increase neurotoxic by-products of dopamine, leading to a greater risk of
Fumarylacetoacetate
Parkinson’s disease and its concomitant cognitive dysfunction.
GSTZ1 and Normative and Non-normative
Cognitive Ageing
Cognitive ageing may be categorised as normative, i.e. non-pathological,
and non-normative, e.g. cognitive decline associated with Alzheimer’s
disease (AD). In fact, even in the presence of moderate AD, some
Fumarate Acetoacetate
cognitive abilities remain stable and indistinguishable from those in a
healthy population.
28
Currently, there is no substantial evidence to
GSTZ1 on telomeres and physical ageing are likely to occur through indicate that GSTZ1 is implicated in non-normative cognitive ageing,
oxidative stress.
18,19
As yet, there is limited evidence for the effects of although there are suggestions that it may predispose to Parkinson’s
oxidative stress genes on normative cognitive ageing.
20,21
disease. The genetic contribution to human cognitive ability, though
thought to be substantial, is yet to be determined adequately.
29
GSTZ1 is
GSTZ1 and Cognitive Studies one among many genes that are each likely to contribute only a small
The non-linear relationship between dopamine concentrations and amount of the variance in cognitive ability in old age. In view of this
cognition forms the background to studies investigating associations genome-wide association, studies may not prove to be very informative.
between functional GSTZ1 polymorphisms and cognitive ability. As noted Instead, more hypothesis-driven, pathway-focused investigations are
above, beyond its actions as a neurotransmitter within the brain, likely to be more fruitful. Such an approach points to future research into
dopamine and its metabolites are hypothesised to have cytotoxic actions genetic polymorphisms of genes that regulate dopamine disposal in
on neurons. Pathways that facilitate the disposal of intracellular
dopamine include oxidative deamination by MAO-A, sequestration into
synaptic vesicles by vesicular monoamine transporter and metabolism of
This alternative model requires more
auto-oxidised products of dopamine by macrophage migration inhibitory
factor, as well as GSTs.
22
An alternative hypothesis to explain the
testing, especially of the effect of other
‘inverted U’ relationship between dopamine levels and cognition is that dopamine by-product pathways and of
at high levels dopamine become neurotoxic, especially due to auto-
the interaction between such disposal
oxidised products.
23
pathway genes and COMT.
One recent study administered a broad cognitive test battery to a cohort
of 470 community volunteers between 64 and 68 years of age from the
1947 Scottish Mental Survey (SMS 1947) residents in the Aberdeen area addition to COMT and MAO. One candidate is the macrophage
with validated childhood IQ data at 11 years of age and whose GSTZ1- migration inhibitory factor gene, which is untested in this regard.
1002 G>A polymorphism was known.
23
There was no significant Another is the vesicular monoamine transporter protein (VMAT2), which
difference between GSTZ1 A-carriers and non-carriers in age 11 IQ is thought to underpin some of the cognitive deficits observed in bipolar
scores, indicating that the polymorphism has no major effect on affective disorder.
30
cognition in childhood. GSTZ1 was significantly associated with the
underlying cognitive trait at age 64–68 years, with A-carriers having Conclusions
mean scores about 3% lower than non-carriers, with a trend towards Hitherto, the predominant paradigm linking dopamine to cognitive ability
performing particularly worse on a test of verbal memory. These findings has focused on its effects as a neurotransmitter. This paradigm has had
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