GSTZ1 Genotype and Cognitive Ability

GSTZ1 Genotype and Cognitive Ability

Quinn Catherine, Starr John M
Published: European Neurology - Volume 3 Issue 2
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The Functions of GSTZ1
Glutathione S-transferases (GSTs) catalyse the nucleophilic conjugation of glutathione with a range of electrophilic substances, which represents a major detoxification mechanism in mammals.1 GST zeta (GSTZ1) catalyses the glutathione-dependent isomerisation of maleylacetoacetate to fumarylacetoacetate in the tyrosine catabolic pathway (see Figure 1). It also catalyses the oxygenation of dichloroacetic acid (DCA) to glyoxylic acid. DCA does not occur naturally but is present in chlorinated water and is potentially neurotoxic.2 Genetic polymorphisms in the coding sequence of GSTZ1 result in significant changes in enzyme function, and it might be expected that this was their major site of action for dopaminergic regulation, but notably they are not implicated in tyrisonaemia, which results from deficiencies of fumarylacetoacetate hydrolase (type 1, most common, affecting the final step of the pathway), tyrosine aminotransferase (type 2, affecting the conversion of tyrosine to p-OH-phenylpyruvic acid) or 4-hydroxyphenylpyruvate dioxygenase (type 3, rare, affecting conversion of p-OH-phenylpyruvic acid to homogentisic acid). Types 2 and 3 are associated with intellectual disability. L-tyrosine is a precursor of dopamine via L-dihydroxyphenylalanine (L-DOPA) and norepinephrine through the action of dopamine β- hydroxylase. Dopamine is also metabolised to the inactive compounds 3,4-dihydroxyphenylacetaldehyde by monoamine oxidase (MAO) and 3- methoxytyramine by catechol-O-methyltransferase (COMT), both ultimately being converted to homovanilic acid. Finally, dopamine can auto-oxidise to 6-hydroxydopamine (6-OHDA), which is neurotoxic, promoting apoptosis.3,4 6-OHDA is commonly used to produce an experimental model of Parkinson’s disease. By-products of dopamine’s auto-oxidation include quinones, free radicals and reactive oxygen species.5 The glutathione redox cycle helps to regulate the equilibrium between dopamine and its oxidated, neurotoxic product 6-OHDA, e.g. by conjugation of glutathione with dopamine-derived quinones.

Dopamine and Cognitive Ability
Dopamine is a major neurotransmitter widely distributed within the brain.6 Dopaminergic neurotransmission in the pre-frontal cortex (PFC) contributes to individual cognitive differences in animals and humans.7 Dopamine is also implicated in cognitive deficits seen in schizophrenia and Parkinson’s disease. Much attention has focused on a functional variation in the human COMT gene that occurs at a single nucleotide polymorphism (SNP) (472G>A), resulting in a valine (Val) to methionine (Met) amino acid substitution (Val158Met). This variant may reduce the thermostability and activity of the enzyme to one-quarter of that encoded by the Val allele,8 although data from human post mortem material suggest that the effect may not be so substantial.9 Reduced enzyme activity may decrease the degradation and increase the concentration of dopamine.7 There is an association between Val/Val COMT Val158Met polymorphism and cognitive ability in healthy adults,10 although data suggest that a shift in the dopamine signalling and PFC function curve occurs with ageing,11 which is an example of the ‘Goldilocks effect’ of having just the right amount of dopamine available. Hence, genetic variants may exert different effects on cognition in youth and old age.

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