2025/10/02 by Wenqin Fu, Saul Landaverde, Xiaoxi Zhuang +1
Biochemistry, Genetics and Molecular Biology · Materials Science · Medicine · #Enzyme Structure and Function #Folate and B Vitamins Research #Metabolism and Genetic Disorders
paper · doi:10.1080/01677063.2025.2591617
openalex publication_date 2025/10/02 · openalex created_date 2025/11/27 · openalex updated_date 2026/07/27
In animals, the enzyme pyridox(am)ine 5’-phosphate oxidase (PNPO) is critical for synthesizing the active form of vitamin B6 (VB6), pyridoxal 5’-phosphate (PLP), from inactive vitamers. PLP is a required cofactor for many enzymatic reactions, including the synthesis of GABA and the monoamines. PNPO disruption in humans is associated with an array of epilepsy syndromes, while Drosophila harboring mutations in the sole PNPO ortholog, sugarlethal (sgll), display spontaneous seizures and shortened lifespans. These phenotypes are suppressed by PLP dietary supplementation and are exacerbated by restriction of dietary B6 vitamers. In the context of PNPO deficiency, it remains to be resolved what the specific contributions by cellular subpopulations in the nervous system are to the neurological phenotypes. We addressed this question in sgll mutants by expressing human PNPO (hPNPO) cDNA in cholinergic, glutamatergic, and GABAergic neurons as well as glia and measuring changes in survival and seizure phenotypes. We found hPNPO expression in GABAergic neurons largely restored lifespan and attenuated seizure activity, while glial expression also improved sgll phenotypes albeit to a lesser degree. In contrast, hPNPO expression in either cholinergic or glutamatergic neurons, accounting for most neurons in the fly brain, did not appreciably alter sgll phenotypes. We contrasted these observations with changes in sgll mutants induced by feeding GABA receptor modulators. The GABAB agonist SKF-97541 reduced mortality, while GABA or GABAA receptor modulators did not improve survival. Together, our data establish a cell-autonomous role for PNPO in GABAergic neurons to support brain function, especially under VB6-restricted conditions.