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

Wardiya Afshar-Saber, Nicole A. Teaney, Kellen D. Winden, Hellen Jumo, Xutong Shi, Gabrielle McGinty, Jed Hubbs, Cidi Chen, Itay Tokatly Latzer, Federico Gasparoli, Darius Ebrahimi-Fakhari, Elizabeth D. Buttermore, Jean Baptiste Roullet, Phillip L. Pearl, Mustafa Sahin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish
Article number106386
JournalNeurobiology of Disease
Volume190
DOIs
StatePublished - Jan 2024

Funding

FundersFunder number
Nikon Imaging Center at Harvard Medical School
SSADH Foundation
National Institutes of HealthR01HD091142
National Institutes of Health
National Institute of Neurological Disorders and StrokeNIH5P30EY012196, U54HD090255, 5K08NS112598
National Institute of Neurological Disorders and Stroke
Baylor College of Medicine

    Keywords

    • Autism spectrum disorder
    • Epilepsy
    • GABA metabolism
    • Mitochondrion
    • Stem cell derived neurons

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