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

• Published in: Neurobiology of disease Vol. 190; p. 106386
• Main Authors: Afshar-Saber, Wardiya, Teaney, Nicole A, Winden, Kellen D, Jumo, Hellen, Shi, Xutong, McGinty, Gabrielle, Hubbs, Jed, Chen, Cidi, Tokatly Latzer, Itay, Gasparoli, Federico, Ebrahimi-Fakhari, Darius, Buttermore, Elizabeth D, Roullet, Jean-Baptiste, Pearl, Phillip L, Sahin, Mustafa
• Format: Journal Article
• Language: English
• Published: United States Elsevier 01.01.2024
• Subjects: Autism spectrum disorder; Epilepsy; GABA metabolism; Mitochondrion; Stem cell derived neurons; Mitochondrion; Stem cell derived neurons; Epilepsy; Autism spectrum disorder; GABA metabolism
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2023.106386

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.