ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations
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 though...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996123004023 |
| _version_ | 1797364229053874176 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Wardiya Afshar-Saber |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T16:32:18Z |
| format | Article |
| id | doaj.art-6afdfd05e9854926bfb6dac05d7d20fc |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-03-08T16:32:18Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-6afdfd05e9854926bfb6dac05d7d20fc2024-01-06T04:38:33ZengElsevierNeurobiology of Disease1095-953X2024-01-01190106386ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterationsWardiya Afshar-Saber0Nicole A. Teaney1Kellen D. Winden2Hellen Jumo3Xutong Shi4Gabrielle McGinty5Jed Hubbs6Cidi Chen7Itay Tokatly Latzer8Federico Gasparoli9Darius Ebrahimi-Fakhari10Elizabeth D. Buttermore11Jean-Baptiste Roullet12Phillip L. Pearl13Mustafa Sahin14Rosamund 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, USARosamund 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, USARosamund 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, USARosamund 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, USAWashington State University, Department of Pharmacotherapy, Spokane, WA, USARosamund 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, USARosamund 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, USARosamund 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, USARosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USADepartment of Cell Biology, Harvard Medical School, Boston, MA, USARosamund 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, USARosamund 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, USAWashington State University, Department of Pharmacotherapy, Spokane, WA, USARosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USARosamund 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.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.http://www.sciencedirect.com/science/article/pii/S0969996123004023EpilepsyAutism spectrum disorderStem cell derived neuronsGABA metabolismMitochondrion |
| spellingShingle | 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 ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations Neurobiology of Disease Epilepsy Autism spectrum disorder Stem cell derived neurons GABA metabolism Mitochondrion |
| title | ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations |
| title_full | ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations |
| title_fullStr | ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations |
| title_full_unstemmed | ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations |
| title_short | ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations |
| title_sort | aldh5a1 deficient ipsc derived excitatory and inhibitory neurons display cell type specific alterations |
| topic | Epilepsy Autism spectrum disorder Stem cell derived neurons GABA metabolism Mitochondrion |
| url | http://www.sciencedirect.com/science/article/pii/S0969996123004023 |
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