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 SSADH-deficient 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.

I. Historical Perspectives and Background

• A. Identification of succinic semialdehyde dehydrogenase deficiency

• B. Human SSADH deficiency: early clinical, metabolic, and enzymatic findings

• C. Pharmacology of GABA and GHB

II. Molecular Genetics of SSADH Deficiency and Functional Polymorphisms of the SSADH Gene

• A. SSADH protein characterization

• B. Molecular genetics of SSADH deficiency–cDNA cloning and pathogenic mutations

• C. Variation in the SSADH gene

• D. Functional polymorphisms in the SSADH gene and evolutionary considerations

III. Tissue and Subcellular Localization of SSADH and Alternative Roles

• A. Localization of SSADH in neural and nonneural tissues

• B. Role of SSADH in 4-hydroxynonenal metabolism

IV. The Clinical Phenotype of SSADH Deficiency: Pathophysiology and Pharmacological Concepts

• A. Clinical phenotype and pharmacologic considerations

• B. Radiographic findings

• C. Neurophysiology and transcranial magnetic stimulation

• D. Treatment strategies and challenges

• E. Status of therapeutic trials

V. Murine Model of SSADH Deficiency

• A. Metabolic findings in the murine model of SSADH deficiency

• B. Disturbances of myelin in SSADH-deficient mouse brain

• C. Neurophysiology and GABAergic abnormalities in SSADH-deficient mice

• D. Evidence of oxidative damage and stress in murine SSADH deficiency

• E. Mechanistic considerations for oxidant stress in SSADH deficiency

• F. Treatment approaches in murine SSADH deficiency

VI. Crystal Structure of SSADH and Novel Regulatory Mechanisms

• A. Enzymatic properties and protein production of SSADH

• B. Crystal structure of the oxidized form of human SSADH

• C. Crystal structure of the reduced form of human SSADH

• D. Redox-switch modulation of human SSADH

• E. SSA and NAD+ binding specificity

• F. Nonredox regulation of E. coli SSADH

VII. Conclusions and Final Remarks