Succinate-semialdehyde dehydrogenase, mitochondrial

ALDH5A1 (succinate-semialdehyde dehydrogenase, mitochondrial) catalyzes a critical step in gamma-aminobutyric acid (GABA) degradation, the final enzymatic reaction converting succinic semialdehyde to succinate (UniProt: P51649). The enzyme is localized to mitochondria and plays a central role in GABAergic neurotransmission homeostasis.

ALDH5A1 is associated with succinic semialdehyde dehydrogenase deficiency (SSADHD; MIM 271980), a rare inborn error of GABA metabolism characterized by accumulation of 4-hydroxybutyric acid and clinical manifestations including developmental delay, intellectual disability, ataxia, seizures, and behavioral disturbances (UniProt: P51649). The enzyme's function in neurotransmitter metabolism positions it within GABAergic and mitochondrial bioenergetic pathways.

In Alzheimer's disease, ALDH5A1 is upregulated in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics). The protein showed a mean log2 fold-change of +0.13 across analyzed subcellular fractions in human post-mortem brain, suggesting altered GABA metabolism may accompany AD pathology. This modest upregulation may reflect compensatory changes in inhibitory neurotransmitter catabolism or mitochondrial stress responses in AD brain.