Abstract
Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5A1 [ALDH5A1]; locus 6p22) occupies a central position in central nervous system (CNS) neurotransmitter metabolism as one of two enzymes necessary for γ-aminobutyric acid (GABA) recycling from the synaptic cleft. Its importance is highlighted by the neurometabolic disease associated with its inherited deficiency in humans, as well as the severe epileptic phenotype observed in Aldh5a1-/- knockout mice. Expanding evidence now suggests, however, that even subtle decreases in human SSADH activity, associated with rare and common single nucleotide polymorphisms, may produce subclinical pathological effects. SSADH, in conjunction with aldo-keto reductase 7A2 (AKR7A2), represent two neural enzymes responsible for further catabolism of succinic semialdehyde, producing either succinate (SSADH) or γ-hydroxybutyrate (GHB; AKR7A2). A GABA analogue, GHB is a short-chain fatty alcohol with unusual properties in the CNS and a long pharmacological history. Moreover, SSADH occupies a further role in the CNS as the enzyme responsible for further metabolism of the lipid peroxidation aldehyde 4-hydroxy-2-nonenal (4-HNE), an intermediate known to induce oxidant stress. Accordingly, subtle decreases in SSADH activity may have the capacity to lead to regional accumulation of neurotoxic intermediates (GHB, 4-HNE). Polymorphisms in SSADH gene structure may also associate with quantitative traits, including intelligence quotient and life expectancy. Further population-based studies of human SSADH activity promise to reveal additional properties of its function and additional roles in CNS tissue.
Highlights
In mammalian brain, g-aminobutyric acid (GABA) is quantitatively the most important inhibitory neurotransmitter, and more than 30 per cent of neurones in the central nervous system (CNS) employ it to mediate inhibitory signalling.[1,2] As for other neurotransmitters, the process of release, reuptake and further metabolism is tightly controlled, tuned to ensure that excitatory/inhibitory transmission maintains equilibrium
For GABA, these processes are mediated by three enzymes: glutamic acid decarboxylase (GAD), which forms GABA from glutamate, and the degradative enzymes GABA transaminase (GABA-T) and aldehyde dehydrogenase 5A1 (ALDH5A1; succinate semialdehyde dehydrogenase [Succinic semialdehyde dehydrogenase (SSADH)]) (Figures 1 and 2)
Human disorders of GAD and GABA-T are rare to non-existent;[3] numerous patients with ALDH5A1 deficiency have been identified since the description of the index patient.[4,5,6]
Summary
G-aminobutyric acid (GABA) is quantitatively the most important inhibitory neurotransmitter, and more than 30 per cent of neurones in the central nervous system (CNS) employ it to mediate inhibitory signalling.[1,2] As for other neurotransmitters, the process of release, reuptake and further metabolism is tightly controlled, tuned to ensure that excitatory/inhibitory transmission maintains equilibrium. Recent data suggest alterations of the GABAA receptor in ALDH5A1 patients, detected using (11C)-flumazenil binding in vivo.[52] studies employing transcranial magnetic stimulation (TMS), which estimates endogenous GABAergic activity, have revealed GABAB receptor abnormalities in human patients.[53] These functional alterations in GABAergic systems, documented in both ALDH5A1-deficient patients and mice (see below), have become the basis for clinical interventions targeting the GABA system in patients.
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