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bioRxiv · 10.1101/2020.06.01.128579

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

Tzou, F.-Y.·Su, T.-Y.·Yu, Y.-L.·Yeh, Y.-H.·Liu, C.-C.·Huang, S.-Y.·Chan, C.-C.
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Abstract

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 disease-associated variant DEGS1H132R. Therefore, DEGS1/ifc deficiency causes dihydroceramide accumulation, resulting in Rac1 translocation and NOX-dependent neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=101 HEIGHT=200 SRC="FIGDIR/small/128579v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@174c3b0org.highwire.dtl.DTLVardef@db65e5org.highwire.dtl.DTLVardef@1fea501org.highwire.dtl.DTLVardef@10318f7_HPS_FORMAT_FIGEXP M_FIG 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. C_FIG 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. HighlightsO_LIDeficiency in dihydroceramide (dhCer) desaturase induces cytoplasmic ROS elevation C_LIO_LIdhCer alters the binding of active Rac1 to reconstituted organelle membranes C_LIO_LIActive Rac1 is enriched in endolysosomes in ifc-KO neurons for ROS genesis C_LIO_LIRac1-NADPH oxidase elicits ROS, degenerating leukodystrophy-related neuronal cells C_LI

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Tzou, F.-Y., Su, T.-Y., Yu, Y.-L., Yeh, Y.-H., Liu, C.-C., Huang, S.-Y., Chan, C.-C.. 2020-06-02. Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress. https://doi.org/10.1101/2020.06.01.128579

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