Lin WH, He M, Fan YN, Baines RA. An RNAi-mediated screen identifies novel
targets for next-generation antiepileptic drugs based on increased expression of
the homeostatic regulator pumilio. J Neurogenet. 2018 May 2:1-12. PMID: 29718742.
From the abstract: "Despite availability of a diverse range of anti-epileptic drugs (AEDs), only
about two-thirds of epilepsy patients respond well to drug treatment. Thus, novel
targets are required to catalyse the design of next-generation AEDs. Manipulation
of neuron firing-rate homoeostasis, through enhancing Pumilio (Pum) activity, has
been shown to be potently anticonvulsant in Drosophila. In this study, we
performed a genome-wide RNAi screen in S2R + cells, using a luciferase-based dPum
activity reporter and identified 1166 genes involved in dPum regulation. Of these
genes, we focused on 699 genes that, on knock-down, potentiate dPum
activity/expression. Of this subgroup, 101 genes are activity-dependent based on
comparison with genes previously identified as activity-dependent by
RNA-sequencing. ... To test for anticonvulsant activity, we utilised an RNA-interference
approach in vivo. RNAi-mediated knockdown showed that 57/101 genes (61%) are
sufficient to significantly reduce seizure duration in the characterized seizure
mutant, para[bss]. ... this study validates Pum as a favourable target for
AED design and, moreover, identifies a number of lead compounds capable of
increasing the expression of this homeostatic regulator."
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