ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations

Neurobiol Dis. 2024 Jan:190:106386. doi: 10.1016/j.nbd.2023.106386. Epub 2023 Dec 16.

Abstract

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. SSADHD leads to impaired GABA metabolism and results in accumulation of GABA and γ-hydroxybutyrate (GHB), which alter neurotransmission and are thought to lead to neurobehavioral symptoms. However, why increased inhibitory neurotransmitters lead to seizures remains unclear. We used induced pluripotent stem cells from SSADHD patients (one female and two male) and differentiated them into GABAergic and glutamatergic neurons. SSADHD iGABA neurons show altered GABA metabolism and concomitant changes in expression of genes associated with inhibitory neurotransmission. In contrast, glutamatergic neurons display increased spontaneous activity and upregulation of mitochondrial genes. CRISPR correction of the pathogenic variants or SSADHD mRNA expression rescue various metabolic and functional abnormalities in human neurons. Our findings uncover a previously unknown role for SSADHD in excitatory human neurons and provide unique insights into the cellular and molecular basis of SSADHD and potential therapeutic interventions.

Keywords: Autism spectrum disorder; Epilepsy; GABA metabolism; Mitochondrion; Stem cell derived neurons.

MeSH terms

  • Amino Acid Metabolism, Inborn Errors* / drug therapy
  • Amino Acid Metabolism, Inborn Errors* / genetics
  • Amino Acid Metabolism, Inborn Errors* / metabolism
  • Developmental Disabilities
  • Female
  • Humans
  • Induced Pluripotent Stem Cells* / metabolism
  • Male
  • Neurons / metabolism
  • Succinate-Semialdehyde Dehydrogenase / deficiency
  • Succinate-Semialdehyde Dehydrogenase / genetics
  • gamma-Aminobutyric Acid / metabolism

Substances

  • gamma-Aminobutyric Acid
  • ALDH5A1 protein, human
  • Succinate-Semialdehyde Dehydrogenase

Supplementary concepts

  • succinic semialdehyde dehydrogenase deficiency