Journal article
Pyridox (am) ine 5'-phosphate oxidase deficiency induces seizures in Drosophila melanogaster
Human molecular genetics, Vol.28(18), pp.3126-3136
09/15/2019
DOI: 10.1093/hmg/ddz143
PMCID: PMC6737294
PMID: 31261385
Abstract
Pyridox (am) ine 5'-phosphate oxidase (PNPO) is a rate-limiting enzyme in converting dietary vitamin B6 (VB6) to pyridoxal 5'-phosphate (PLP), the biologically active form of VB6 and involved in the synthesis of neurotransmitters including γ-aminobutyric acid (GABA), dopamine, and serotonin. In humans, PNPO mutations have been increasingly identified in neonatal epileptic encephalopathy and more recently also in early-onset epilepsy. Till now, little is known about the neurobiological mechanisms underlying PNPO-deficiency-induced seizures due to the lack of animal models. Previously, we identified a c.95 C>A missense mutation in sugarlethal (sgll)-the Drosophila homolog of human PNPO (hPNPO)-and found mutant (sgll95) flies exhibiting a lethal phenotype on a diet devoid of VB6. Here, we report the establishment of both sgll95 and ubiquitous sgll knockdown (KD) flies as valid animal models of PNPO-deficiency-induced epilepsy. Both sgll95 and sgll KD flies exhibit spontaneous seizures before they die. Electrophysiological recordings reveal that seizures caused by PNPO deficiency have characteristics similar to that in flies treated with the GABA antagonist picrotoxin. Both seizures and lethality are associated with low PLP levels and can be rescued by ubiquitous expression of wild-type sgll or hPNPO, suggesting the functional conservation of the PNPO enzyme between humans and flies. Results from cell type-specific sgll KD further demonstrate that PNPO in the brain is necessary for seizure prevention and survival. Our establishment of the first animal model of PNPO deficiency will lead to better understanding of VB6 biology, the PNPO gene and its mutations discovered in patients, and can be a cost-effective system to test therapeutic strategies.
Details
- Title: Subtitle
- Pyridox (am) ine 5'-phosphate oxidase deficiency induces seizures in Drosophila melanogaster
- Creators
- Wanhao Chi - Department of Neurobiology, University of Chicago, Chicago, IL, USAAtulya S R Iyengar - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA, USAMonique Albersen - Section Metabolic Diagnostics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, EA, The NetherlandsMarjolein Bosma - Section Metabolic Diagnostics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, EA, The NetherlandsNanda M Verhoeven-Duif - Section Metabolic Diagnostics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, EA, The NetherlandsChun-Fang Wu - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA, USAXiaoxi Zhuang - Department of Neurobiology, University of Chicago, Chicago, IL, USA
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.28(18), pp.3126-3136
- Publisher
- England
- DOI
- 10.1093/hmg/ddz143
- PMID
- 31261385
- PMCID
- PMC6737294
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Grant note
- R01 GM100768 / NIGMS NIH HHS T32 DA043469 / NIDA NIH HHS
- Language
- English
- Date published
- 09/15/2019
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984070424902771
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