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

被引：8

作者：

Afshar-Saber, Wardiya ^{[1
,2
]}

Teaney, Nicole A. ^{[1
,2
]}

Winden, Kellen D. ^{[1
,2
]}

Jumo, Hellen ^{[1
,2
]}

Shi, Xutong ^{[3
]}

Mcginty, Gabrielle ^{[1
,2
]}

Hubbs, Jed ^{[1
,2
]}

Chen, Cidi ^{[1
,2
,5
]}

Latzer, Itay Tokatly ^{[1
,6
]}

Gasparoli, Federico ^{[4
]}

Ebrahimi-Fakhari, Darius ^{[1
,2
]}

Buttermore, Elizabeth D. ^{[1
,2
,5
]}

Roullet, Jean-Baptiste ^{[3
]}

Pearl, Phillip L. ^{[1
]}

Sahin, Mustafa ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Boston Childrens Hosp, Rosamund Stone Zander Translat Neurosci Ctr, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston Childrens Hosp, FM Kirby Neurobiol Ctr, Dept Neurol, Boston, MA USA

[3] Washington State Univ, Dept Pharmacotherapy, Spokane, WA USA

[4] Harvard Med Sch, Dept Cell Biol, Boston, MA USA

[5] Boston Childrens Hosp, Rosamund Stone Zander Translat Neurosci Ctr, Human Neuron Core, Boston, MA USA

[6] Tel Aviv Univ, Fac Med, Tel Aviv, Israel

来源：

NEUROBIOLOGY OF DISEASE | 2024年 / 190卷

关键词：

Epilepsy; Autism spectrum disorder; Stem cell derived neurons; GABA metabolism; Mitochondrion; SEMIALDEHYDE DEHYDROGENASE-DEFICIENCY; DISORDER; ACID; VIGABATRIN; PHENOTYPE; DYNAMICS; PLATFORM;

D O I：

10.1016/j.nbd.2023.106386

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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 gamma-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.

引用

页数：15

共 36 条

[1] α4βδ GABAA receptors are high-affinity targets for γ-hydroxybutyric acid (GHB) [J].

Absalom, Nathan ;

Eghorn, Laura F. ;

Villumsen, Inge S. ;

Karim, Nasiara ;

Bay, Tina ;

Olsen, Jesper V. ;

Knudsen, Gitte M. ;

Brauner-Osborne, Hans ;

Frolund, Bente ;

Clausen, Rasmus P. ;

Chebib, Mary ;

Wellendorph, Petrine .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (33) :13404-13409

[2] Comparative cellular analysis of motor cortex in human, marmoset and mouse [J].

Bakken, Trygve E. ;

Jorstad, Nikolas L. ;

Hu, Qiwen ;

Lake, Blue B. ;

Tian, Wei ;

Kalmbach, Brian E. ;

Crow, Megan ;

Hodge, Rebecca D. ;

Krienen, Fenna M. ;

Sorensen, Staci A. ;

Eggermont, Jeroen ;

Yao, Zizhen ;

Aevermann, Brian D. ;

Aldridge, Andrew I. ;

Bartlett, Anna ;

Bertagnolli, Darren ;

Casper, Tamara ;

Castanon, Rosa G. ;

Crichton, Kirsten ;

Daigle, Tanya L. ;

Dalley, Rachel ;

Dee, Nick ;

Dembrow, Nikolai ;

Diep, Dinh ;

Ding, Song-Lin ;

Dong, Weixiu ;

Fang, Rongxin ;

Fischer, Stephan ;

Goldman, Melissa ;

Goldy, Jeff ;

Graybuck, Lucas T. ;

Herb, Brian R. ;

Hou, Xiaomeng ;

Kancherla, Jayaram ;

Kroll, Matthew ;

Lathia, Kanan ;

van Lew, Baldur ;

Li, Yang Eric ;

Liu, Christine S. ;

Liu, Hanqing ;

Lucero, Jacinta D. ;

Mahurkar, Anup ;

McMillen, Delissa ;

Miller, Jeremy A. ;

Moussa, Marmar ;

Nery, Joseph R. ;

Nicovich, Philip R. ;

Niu, Sheng-Yong ;

Orvis, Joshua ;

Osteen, Julia K. .

NATURE, 2021, 598 (7879) :111-+

[3]

Casarano M, 2012, JIMD REP, V2, P119, DOI 10.1007/8904_2011_60

[4] Mitochondrial signalling and homeostasis: from cell biology to neurological disease [J].

Collier, Jack J. ;

Olahova, Monika ;

McWilliams, Thomas G. ;

Taylor, Robert W. .

TRENDS IN NEUROSCIENCES, 2023, 46 (02) :137-152

[5] Absence seizures in succinic semialdehyde dehydrogenase deficient mice: a model of juvenile absence epilepsy [J].

Cortez, MA ;

Wu, Y ;

Gibson, KM ;

Snead, OC .

PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 2004, 79 (03) :547-553

[6] Age-related phenotype and biomarker changes in SSADH deficiency [J].

DiBacco, Melissa L. ;

Roullet, Jean-Baptiste ;

Kapur, Kush ;

Brown, Madalyn N. ;

Walters, Dana C. ;

Gibson, K. Michael ;

Pearl, Phillip L. .

ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY, 2019, 6 (01) :114-120

[7]

Ebrahimi-Fakhari D, 2016, CELL REP, V17, P1053, DOI [10.1016/j.celrep.2016.10.051, 10.1016/j.celrep.2016.09.054]

[8] Aberrant GABAA Receptor-Mediated Inhibition in Cortico-Thalamic Networks of Succinic Semialdehyde Dehydrogenase Deficient Mice [J].

Errington, Adam C. ;

Gibson, K. Michael ;

Crunelli, Vincenzo ;

Cope, David W. .

PLOS ONE, 2011, 6 (04)

[9] Murine succinate semialdehyde dehydrogenase (SSADH) deficiency, a heritable disorder of GABA metabolism with epileptic phenotype [J].

Gibson, KM ;

Jakobs, C ;

Pearl, PL ;

Snead, OC .

IUBMB LIFE, 2005, 57 (09) :639-644

[10] 4-hydroxybutyric acid and the clinical phenotype of succinic semialdehyde dehydrogenase deficiency, an inborn error of GABA metabolism [J].

Gibson, KM ;

Hoffmann, GF ;

Hodson, AK ;

Bottiglieri, T ;

Jakobs, C .

NEUROPEDIATRICS, 1998, 29 (01) :14-22

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