In vitro modeling of experimental succinic semialdehyde dehydrogenase deficiency (SSADHD) using brain-derived neural stem cells

Kara R. Vogel, Garrett R. Ainslie, Erwin E. Jansen, Gajja S. Salomons, Jean-Baptiste Roullet, K. Michael Gibson

Research output: Contribution to journalArticle

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Abstract

We explored the utility of neural stem cells (NSCs) as an in vitro model for evaluating preclinical therapeutics in succinic semialdehyde dehydrogenase-deficient (SSADHD) mice. NSCs were obtained from aldh5a1+/+ and aldh5a1-/- mice (aldh5a1 = aldehyde dehydrogenase 5a1 = SSADH). Multiple parameters were evaluated including: (1) production of GHB (γ-hydroxybutyrate), the biochemical hallmark of SSADHD; (2) rescue from cell death with the dual mTOR (mechanistic target of rapamycin) inhibitor, XL-765, an agent previously shown to rescue aldh5a1-/- mice from premature lethality; (3) mitochondrial number, total reactive oxygen species, and mitochondrial superoxide production, all previously documented as abnormal in aldh5a1-/- mice; (4) total ATP levels and ATP consumption; and (5) selected gene expression profiles associated with epilepsy, a prominent feature in both experimental and human SSADHD. Patterns of dysfunction were observed in all of these parameters and mirrored earlier findings in aldh5a1-/- mice. Patterns of dysregulated gene expression between hypothalamus and NSCs centered on ion channels, GABAergic receptors, and inflammation, suggesting novel pathomechanisms as well as a developmental ontogeny for gene expression potentially associated with the murine epileptic phenotype. The NSC model of SSADHD will be valuable in providing a first-tier screen for centrally-acting therapeutics and prioritizing therapeutic concepts of preclinical animal studies applicable to SSADHD.

Original languageEnglish (US)
Article numbere0186919
JournalPLoS One
Volume12
Issue number10
DOIs
StatePublished - Oct 1 2017
Externally publishedYes

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succinate dehydrogenase (quinone)
Succinate-Semialdehyde Dehydrogenase
Neural Stem Cells
Stem cells
stem cells
Brain
brain
Gene expression
mice
gene expression
therapeutics
Adenosine Triphosphate
Hydroxybutyrates
Developmental Genes
Gene Expression
Aldehyde Dehydrogenase
aldehyde dehydrogenase
Cell death
Sirolimus
Ion Channels

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Vogel, K. R., Ainslie, G. R., Jansen, E. E., Salomons, G. S., Roullet, J-B., & Gibson, K. M. (2017). In vitro modeling of experimental succinic semialdehyde dehydrogenase deficiency (SSADHD) using brain-derived neural stem cells. PLoS One, 12(10), [e0186919]. https://doi.org/10.1371/journal.pone.0186919

In vitro modeling of experimental succinic semialdehyde dehydrogenase deficiency (SSADHD) using brain-derived neural stem cells. / Vogel, Kara R.; Ainslie, Garrett R.; Jansen, Erwin E.; Salomons, Gajja S.; Roullet, Jean-Baptiste; Gibson, K. Michael.

In: PLoS One, Vol. 12, No. 10, e0186919, 01.10.2017.

Research output: Contribution to journalArticle

Vogel, Kara R. ; Ainslie, Garrett R. ; Jansen, Erwin E. ; Salomons, Gajja S. ; Roullet, Jean-Baptiste ; Gibson, K. Michael. / In vitro modeling of experimental succinic semialdehyde dehydrogenase deficiency (SSADHD) using brain-derived neural stem cells. In: PLoS One. 2017 ; Vol. 12, No. 10.
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