DEGS1 variant causes neurological disorder

Dolgin, Vadim; Straussberg, Rachel; Xu, Ruijuan; Mileva, Izolda; Yogev, Yuval; Khoury, Raed; Konen, Osnat; Barhum, Yael; Zvulunov, Alex; Mao, Cungui; Birk, Ohad S.

doi:10.1038/s41431-019-0444-z

Cited by 31 publications

(29 citation statements)

References 19 publications

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“…In the brain, it is primarily expressed in the cerebellum, medulla, and hippocampus, with only small expression in the cortex and striatum. In humans, a homozygous missense mutation in DEGS1 was associated with a severe regressive neurological disease condition including intellectual disability, spastic paraplegia, and epilepsy 40 . Its specific function in the brain is currently unknown, but it may also be involved in the fine regulation of the balance between sphingolipids and dihydrosphingolipids 41 …”

Section: Discussionmentioning

confidence: 99%

Cocaine attenuates acid sphingomyelinase activity during establishment of addiction‐related behavior—A translational study in rats and monkeys

et al. 2020

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Cocaine addiction is a severe psychiatric condition for which currently no effective pharmacotherapy is available. Brain mechanisms for the establishment of addiction‐related behaviors are still not fully understood, and specific biomarkers for cocaine use are not available. Sphingolipids are major membrane lipids, which shape neuronal membrane composition and dynamics in the brain. Here, we investigated how chronic cocaine exposure during establishment of addiction‐related behaviors affects the activity of the sphingolipid rheostat controlling enzymes in the brain of rats. As we detected specific effects on several enzymes in the brain, we tested whether the activity of selected enzymes in the blood may serve as potential biomarker for cocaine exposure in non‐human primates (Callithrix penicillata). We found that intravenous cocaine self‐administration led to a reduced mRNA expression of Cers1, Degs1 and Degs2, and Smpd1 in the prefrontal cortex of rats, as well as a reduction of Cers4 expression in the striatum. These effects reversed after 10 days of abstinence. Monkeys showed a robust cocaine‐induced place preference (CPP). This coincided with a reduction in blood acid sphingomyelinase (ASM) activity after CPP establishment. This effect normalized after 15 days of abstinence. Altogether, these findings suggest that the establishment of cocaine addiction‐related behaviors coincides with changes in the activity of sphingolipid controlling enzymes. In particular, blood ASM levels may serve as a translational biomarker for recent cocaine exposure.

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Section: Discussionmentioning

confidence: 99%

Cocaine attenuates acid sphingomyelinase activity during establishment of addiction‐related behavior—A translational study in rats and monkeys

et al. 2020

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“…Jung et al (2017) show that eye-specific ifc-KO results in activity-dependent neurodegeneration and demonstrated that ifc can function cell non-autonomously. Inherited DEGS1 deficiencies lead to hypomyelination in the central and peripheral nervous systems (Dolgin et al, 2019, Karsai et al, 2019, Pant et al, 2019). Since exosomes are important for myelination and demyelination, whether altered exosome production is the underlying cause of defects seen in patients with inherited DEGS1 deficiencies warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Three recent reports linked variants of the human dhCer desaturase gene, DEGS1 , to leukodystrophy and systemic neuropathy (Dolgin et al, 2019, Karsai et al, 2019, Pant et al, 2019). These reports not only confirm an essential role for DEGS1 in the human nervous system, but they also showed that loss-of-function mutations of DEGS1 cause significant accumulation of dhCer and a shift of cellular sphingolipid pool towards the dihydro forms.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, genetic or drug inhibition of DEGS1/Ifc has been shown to cause significant accumulation of dhCer which increases reactive oxygen species, induces autophagy and ER stress, causes cell cycle arrest, and even results in cell death in experimental models (Lee et al, 2012). In humans, variants of the human dhCer desaturase gene, DEGS1, have recently been linked to hypomyelinating leukodystrophy and systemic neuropathy (Dolgin et al, 2019, Karsai et al, 2019, Pant et al, 2019). These reports not only confirm an essential role for DEGS1 in the human nervous system, but also show that loss-of-function mutations of DEGS1cause significant accumulation of dhCer and an overall shift of cellular sphingolipid pool towards the dihydro forms (Karsai et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production

Jhang

Lin

et al. 2020

Preprint

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Exosomes play important roles in the nervous system. Mutations in the human dihydroceramide desaturase gene, DEGS1, are recently linked to severe neurological disorders, but the cause remains unknown. Here, we show that Ifc is required for the morphology and function of Drosophila photoreceptor neurons and not in the surrounding glia, but the degeneration of ifc-KO eyes can be rescued by glial expression of ifc, possibly mediated by exosomes. We develop an in vivo assay using Drosophila eye imaginal discs and show that the level and activity of Ifc correlates with the detection of exosome-like vesicles. While ifc overexpression and autophagy inhibition both enhances exosome production, combining the two had no additive effect. Moreover, ifc-KO reduces the density of the exosome precursor intraluminal vesicles (ILVs) in vivo, and DEGS1 promotes ILV formation in vitro. In conclusion, dihydroceramide desaturase promotes exosome formation and prevents its autophagic degradation in the nervous system.

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“…Notably, the defects of ifc-KO flies were rescued by overexpression of a human homolog, DEGS1, suggesting functional conservation between fly and human. In 2019, three independent investigations described the association of DEGS1 loss-of-function variants with leukodystrophy and systemic neuropathy (Dolgin et al, 2019;Karsai et al, 2019;Pant et al, 2019). Despite the clinical descriptions in patients and phenotypic characterization of the fly model, the pathophysiological role of ifc/DEGS1 and dihydroceramide in the nervous system remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

Tzou

et al. 2020

Preprint

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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.

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DEGS1 variant causes neurological disorder

Cited by 31 publications

References 19 publications

Cocaine attenuates acid sphingomyelinase activity during establishment of addiction‐related behavior—A translational study in rats and monkeys

Cocaine attenuates acid sphingomyelinase activity during establishment of addiction‐related behavior—A translational study in rats and monkeys

Dihydroceramide desaturase promotes the formation of intraluminal vesicles and inhibits autophagy to increase exosome production

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

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