Succinic Semialdehyde Dehydrogenase: Biochemical–Molecular–Clinical Disease Mechanisms, Redox Regulation, and Functional Significance

Abstract

Succinic semialdehyde dehydrogenase (SSADH; aldehyde dehydrogenase 5a1, ALDH5A1; E.C. 1.2.1.24; OMIM 610045, 271980) deficiency is a rare heritable disorder that disrupts the metabolism of the inhibitory neurotransmitter 4-aminobutyric acid (GABA). Identified in conjunction with increased urinary excretion of the GABA analog gamma-hydroxybutyric acid (GHB), numerous patients have been identified worldwide and the autosomal-recessive disorder has been modeled in mice. The phenotype is one of nonprogressive neurological dysfunction in which seizures may be prominently displayed. The murine model is a reasonable phenocopy of the human disorder, yet the severity of the seizure disorder in the mouse exceeds that observed in SSADHdeficient patients. Abnormalities in GABAergic and GHBergic neurotransmission, documented in patients and mice, form a component of disease pathophysiology, although numerous other disturbances (metabolite accumulations, myelin abnormalities, oxidant stress, neurosteroid depletion, altered bioenergetics, etc.) are also likely to be involved in developing the disease phenotype. Most recently, the demonstration of a redox control system in the SSADH protein active site has provided new insights into the regulation of SSADH by the cellular oxidation=reduction potential. The current review summarizes some 30 years of research on this protein and disease, addressing pathological mechanisms in human and mouse at the protein, metabolic, molecular, and whole-animal level. Antioxid. Redox Signal. 15, 691-718.

Structural Basis for a Cofactor-dependent Oxidation Protection and Catalysis of Cyanobacterial Succinic Semialdehyde Dehydrogenase

“…SSADHs are ubiquitous in a wide range of organisms, including humans, bacteria, plants, and mammals. In eukaryotes, mitochondrial SSADH plays a crucial role in the ␥-aminobutyrate shunt (1,2), where it is responsible for the final reaction in the shunt and thus provides the carbon contained in ␥-aminobutyrate as a form of succinate to the ATPgenerating tricarboxylic acid (TCA) cycle. Mutation-induced malfunction or a deficiency in SSADH activity has been attributed to an uncommon and heritable neuropharmacological disorder in humans (3).…”

Aldehyde Dehydrogenase Inhibitors: a Comprehensive Review of the Pharmacology, Mechanism of Action, Substrate Specificity, and Clinical Application

“…ALDH activity is crucial to the biosynthesis of retinoic acid, an important regulator of vertebrate development, and to the metabolism of the neurotransmitter GABA (Yoshida et al, 1992;Vasiliou et al, 2000;Sophos and Vasiliou, 2003;Vasiliou and Nebert, 2005;Marchitti et al, 2008;Niederreither and Dollé, 2008;Kim et al, 2011a). From the toxicological point of view, dehydrogenase enzymatic activity of ALDHs is important in alcohol metabolism through aldehyde detoxification and for cellular homeostasis by eliminating reactive aldehydes derived from lipid peroxidation (Vasiliou et al, 2000).…”

Efficacy of Vigabatrin Intervention in a Mild Phenotypic Expression of Succinic Semialdehyde Dehydrogenase Deficiency

“…Other typical signs and symptoms include axial hypotonia, ataxia, movement disorder such as dystonia or choreoatetosis and epilepsy (Knerr et al 2007). Psychiatric symptoms may be the most disabling and are manifest by hyperkineticism, inattention and sometimes aggression in early childhood, anxiety, and obsessive-compulsive disorder in adolescence and adulthood (Kim et al 2010).…”

“…The SSADH gene (ALDH5A1) has been mapped on chromosome 6p22 (Trettel et al 1997;Blasi et al 2002) and multiple different mutations have been identified (Gibson et al 1997;Gibson and Jakobs 2001;Akaboshi et al 2003) in approximately 450 patients thus far diagnosed (Jakobs et al 1981;Kim et al 2010). The clinical picture of SSADH deficiency is highly heterogeneous, characterized by neurological symptoms including such as varying degrees of mental retardation, seizures, hypotonia, ataxia, and developmental language delay.…”

“…Proton spectroscopy has variably revealed elevated levels of GABA and GHB in the white and gray matter (Ethofer et al 2004;Kim et al 2010).…”