Allnighter pseudokinase-mediated feedback links proteostasis and sleep in Drosophila

Shashank Shekhar (), Andrew T. Moehlman, Brenden Park, Michael Ewnetu, Charles Tracy, Iris Titos, Krzysztof Pawłowski, Vincent S. Tagliabracci and Helmut Krämer ()
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Shashank Shekhar: UT Southwestern Medical Center, Dallas, TX; O’Donnell Brain Institute
Andrew T. Moehlman: UT Southwestern Medical Center, Dallas, TX; O’Donnell Brain Institute
Brenden Park: Department of Molecular Biology UT Southwestern Medical Center
Michael Ewnetu: UT Southwestern Medical Center, Dallas, TX; O’Donnell Brain Institute
Charles Tracy: UT Southwestern Medical Center, Dallas, TX; O’Donnell Brain Institute
Iris Titos: School of Medicine
Krzysztof Pawłowski: Department of Molecular Biology UT Southwestern Medical Center
Vincent S. Tagliabracci: Department of Molecular Biology UT Southwestern Medical Center
Helmut Krämer: UT Southwestern Medical Center, Dallas, TX; O’Donnell Brain Institute

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract In nervous systems, retrograde signals are key for organizing circuit activity and maintaining neuronal homeostasis. We identify the conserved Allnighter (Aln) pseudokinase as a cell non-autonomous regulator of proteostasis responses necessary for normal sleep and structural plasticity of Drosophila photoreceptors. In aln mutants exposed to extended ambient light, proteostasis is dysregulated and photoreceptors develop striking, but reversible, dysmorphology. The aln gene is widely expressed in different neurons, but not photoreceptors. However, secreted Aln protein is retrogradely endocytosed by photoreceptors. Inhibition of photoreceptor synaptic release reduces Aln levels in lamina neurons, consistent with secreted Aln acting in a feedback loop. In addition, aln mutants exhibit reduced night time sleep, providing a molecular link between dysregulated proteostasis and sleep, two characteristics of ageing and neurodegenerative diseases.

Date: 2023
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DOI: 10.1038/s41467-023-38485-7

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