Highlights d Lack of dihydroceramide desaturase activity induces cytoplasmic ROS d Rac1-NADPH oxidase-elicited ROS mediates leukodystrophy-related neuronal death d DEGS1/ifc defects cause mislocalization of Rac1 to the endolysosomes d Dihydroceramide alters binding of active Rac1 to reconstituted organelle membranes

Autophagy regulates cellular homeostasis by degrading and recycling cytosolic components and damaged organelles. Disruption of autophagic flux has been shown to induce or facilitate neurodegeneration and accumulation of autophagic vesicles is overt in neurodegenerative diseases. The fruit fly Drosophila has been used as a model system to identify new factors that regulate physiology and disease. Here we provide a historical perspective of how the fly models have offered mechanistic evidence to understand the role of autophagy in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Charcot-Marie-Tooth neuropathy, and polyglutamine disorders. Autophagy also plays a pivotal role in maintaining tissue homeostasis and protecting organism health. The gastrointestinal tract regulates organism health by modulating food intake, energy balance, and immunity. Growing evidence is strengthening the link between autophagy and digestive tract health in recent years. Here, we also discuss how the fly models have advanced the understanding of digestive physiology regulated by autophagy.

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Dihydroceramide and NeurodegenerationTzou et al. Highlights  Deficiency in dihydroceramide (dhCer) desaturase induces cytoplasmic ROS elevation  dhCer alters the binding of active Rac1 to reconstituted organelle membranes  Active Rac1 is enriched in endolysosomes in ifc-KO neurons for ROS genesis  Rac1-NADPH oxidase elicits ROS, degenerating leukodystrophy-related neuronal cells Dihydroceramide and Neurodegeneration Tzou et al. Summary Disruption of sphingolipid homeostasis has been shown to cause neurological disorders. How specific sphingolipid species modulate the pathogenesis remains unknown. The last step of sphingolipid de novo synthesis is the conversion of dihydroceramide to ceramide catalyzed by dihydroceramide desaturase (human DEGS1; Drosophila Ifc). Loss of ifc leads to dihydroceramide accumulation and oxidative stress, resulting in photoreceptors degeneration, while DEGS1 variants were associated with leukodystrophy and neuropathy. Here, we demonstrated that ifc regulates Rac1 compartmentalization in fly photoreceptors and further showed that dihydroceramide alters the association of active Rac1 to membranes mimicking specific organelles. We also revealed that the major source of ROS originated from Rac1 and NADPH oxidase (NOX) in the cytoplasm, as the NOX inhibitor apocynin ameliorated the oxidative stress and functional defects in both fly ifc-KO photoreceptors and human neuronal cells with diseaseassociated variant DEGS1 H132R . Therefore, DEGS1/ifc deficiency causes dihydroceramide accumulation, resulting in Rac1 translocation and NOXdependent neurodegeneration. Dihydroceramide and Neurodegeneration Tzou et al. Graphical Abstract A DEGS1/ifc converts dihydroceramide to ceramide in neuronal cells, and the endolysosomal NOX complex is not activated. B Dihydroceramide accumulates without functional DEGS1/ifc and causes alterations in membrane microdomains and recruits active Rac1 to endolysosomes. The activation of endolysosomal Rac1-NOX complex elevates cytosolic ROS levels, causing neurodegeneration. Dihydroceramide and Neurodegeneration Tzou et al. In Brief (eTOC blurb) Deficiency in dihydroceramide desaturase causes oxidative stress-mediated neurological disorders. Tzou and Su et al. show that increased dihydroceramide causes the relocalization of active Rac1, whilst inhibition of the Rac1-NOX ameliorates the oxidative stress and neuronal defects. NOX inhibitor apocynin may provide new direction of treatments for patients with DEGS1 variants. Keywords: DEGS1/dihydroceramide/neurodegeneration/oxidative stress/Rac1 signaling Dihydroceramide and Neurodegeneration Tzou et al.