Loss of Atg16 delays the alcohol-induced sedation response via regulation of Corazonin neuropeptide production in Drosophila.

Kata Varga,Péter Nagy,Attila L. Kovács,Katarina Arsikin Csordás,Krisztina Hegedűs,Gábor Juhász

doi:10.1038/srep34641

Abstract

Autophagy defects lead to the buildup of damaged proteins and organelles, reduced survival during starvation and infections, hypersensitivity to stress and toxic substances, and progressive neurodegeneration. Here we show that, surprisingly, Drosophila mutants lacking the core autophagy gene Atg16 are not only defective in autophagy but also exhibit increased resistance to the sedative effects of ethanol, unlike Atg7 or Atg3 null mutant flies. This mutant phenotype is rescued by the re-expression of Atg16 in Corazonin (Crz)-producing neurosecretory cells that are known to promote the sedation response during ethanol exposure, and RNAi knockdown of Atg16 specifically in these cells also delays the onset of ethanol-induced coma. We find that Atg16 and Crz colocalize within these neurosecretory cells, and both Crz protein and mRNA levels are decreased in Atg16 mutant flies. Thus, Atg16 promotes Crz production to ensure a proper organismal sedation response to ethanol.

Highlights

Is thought to function similar to an E3 enzyme by promoting the final step of Atg8a lipidation[9]
We show that Atg[16] function in ethanol sensitivity maps to Corazonin-producing neurosecretory cells located in the pars lateralis using cell type-specific genetic rescue and RNAi experiments, and that Atg[16] deficiency impairs Corazonin production
We found large-scale accumulation of p62 ( known as Ref(2)P in flies), the selective autophagy cargo and ubiquitinated protein receptor[8,12], in both Atg16d67 and Atg16d129 mutants compared to controls

Summary

Introduction

Is thought to function similar to an E3 enzyme by promoting the final step of Atg8a lipidation[9]. In this work we generated null mutants for Drosophila Atg[16] These animals exhibit the expected autophagy defects and as a consequence, the accumulation of neuronal protein aggregates, climbing defects, sensitivity to the oxidative stress-inducing toxin paraquat, and short lifespan. We show that Atg[16] function in ethanol sensitivity maps to Corazonin-producing neurosecretory cells located in the pars lateralis using cell type-specific genetic rescue and RNAi experiments, and that Atg[16] deficiency impairs Corazonin production. These data reveal an unexpected new role for Atg[16] in this popular animal model

Methods

Results

Conclusion