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ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations.
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.
Affiliation
  • Afshar-Saber W; 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.
  • Teaney NA; 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.
  • Winden KD; 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.
  • Jumo H; 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.
  • Shi X; Washington State University, Department of Pharmacotherapy, Spokane, WA, USA.
  • McGinty G; 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.
  • Hubbs J; 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.
  • Chen C; 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 Translati
  • Tokatly Latzer I; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  • Gasparoli F; Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
  • Ebrahimi-Fakhari D; 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.
  • Buttermore ED; 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 Translati
  • Roullet JB; Washington State University, Department of Pharmacotherapy, Spokane, WA, USA.
  • Pearl PL; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • Sahin M; 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. Electronic address: Mustafa.sahin@childrens.harvar
Neurobiol Dis ; 190: 106386, 2024 Jan.
Article in En | MEDLINE | ID: mdl-38110041
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.
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Full text: 1 Database: MEDLINE Main subject: Induced Pluripotent Stem Cells / Amino Acid Metabolism, Inborn Errors Limits: Female / Humans / Male Language: En Year: 2024 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Induced Pluripotent Stem Cells / Amino Acid Metabolism, Inborn Errors Limits: Female / Humans / Male Language: En Year: 2024 Type: Article