Succinic semialdehyde dehydrogenase: biochemical-molecular-clinical disease mechanisms, redox regulation, and functional significance.
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.
Kim
Kyung-Jin
KJ
Pohang Accelerator Laboratory, Pohang University of Science and Technology, Pohang, Republic of Korea.
Pearl
Phillip L
PL
Jensen
Kimmo
K
Snead
O Carter
OC
Malaspina
Patrizia
P
Jakobs
Cornelis
C
Gibson
K Michael
KM
D000447:Aldehydes / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000818:Animals; D020134:Catalytic Domain; D002658:Developmental Disabilities; D004195:Disease Models, Animal; D006801:Humans; D006885:Hydroxybutyrates / Q000652:urine; D051379:Mice; D010084:Oxidation-Reduction; D050644:Succinate-Semialdehyde Dehydrogenase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000447:Aldehydes; D006885:Hydroxybutyrates; C111420:4-hydroxybutyric acid; D005680:gamma-Aminobutyric Acid; D050644:Succinate-Semialdehyde Dehydrogenase; C027576:4-hydroxy-2-nonenal