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

Neurobiology of Disease (Jan 2024)

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

Affiliations

Wardiya Afshar-Saber: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Nicole A. Teaney: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Kellen D. Winden: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Hellen Jumo: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Xutong Shi: Washington State University, Department of Pharmacotherapy, Spokane, WA, USA
Gabrielle McGinty: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Jed Hubbs: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Cidi Chen: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Human Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA, USA
Itay Tokatly Latzer: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Federico Gasparoli: Department of Cell Biology, Harvard Medical School, Boston, MA, USA
Darius Ebrahimi-Fakhari: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Elizabeth D. Buttermore: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Human Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA, USA
Jean-Baptiste Roullet: Washington State University, Department of Pharmacotherapy, Spokane, WA, USA
Phillip L. Pearl: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
Mustafa Sahin: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; FM Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Corresponding author at: Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Journal volume & issue: Vol. 190
p. 106386

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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Abstract

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