Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons
| Autor: | John Dunlop, Wei Shen, Zdenek Berger, Kewa Mou, Katrina L. Paumier, Li Li, Warren D. Hirst, Anastasia G. Henry |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Pyrrolidines Huntingtin Meperidine Endosome Blotting Western Primary Cell Culture Mutant Mice Transgenic Real-Time Polymerase Chain Reaction Biochemistry Glycosphingolipids Dioxanes Pathogenesis Mice Cellular and Molecular Neuroscience Lysosome Autophagy medicine Animals Humans Enzyme Inhibitors Phosphorylation RNA Small Interfering Cells Cultured PI3K/AKT/mTOR pathway Mice Knockout Neurons ATP synthase biology Parkinson Disease Cell biology Oncogene Protein v-akt HEK293 Cells medicine.anatomical_structure Glucosyltransferases biology.protein Female |
| Zdroj: | Journal of Neurochemistry. 129:884-894 |
| ISSN: | 0022-3042 |
| Popis: | Aggregate-prone mutant proteins, such as α-synuclein and huntingtin, play a prominent role in the pathogenesis of various neurodegenerative disorders; thus, it has been hypothesized that reducing the aggregate-prone proteins may be a beneficial therapeutic strategy for these neurodegenerative disorders. Here, we identified two previously described glucosylceramide (GlcCer) synthase inhibitors, DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol and Genz-123346(Genz), as enhancers of autophagy flux. We also demonstrate that GlcCer synthase inhibitors exert their effects on autophagy by inhibiting AKT-mammalian target of rapamycin (mTOR) signaling. More importantly, siRNA knock down of GlcCer synthase had the similar effect as pharmacological inhibition, confirming the on-target effect. In addition, we discovered that inhibition of GlcCer synthase increased the number and size of lysosomal/late endosomal structures. Although inhibition of GlcCer synthase decreases levels of mutant α-synuclein in neurons, it does so, according to our data, through autophagy-independent mechanisms. Our findings demonstrate a direct link between glycosphingolipid biosynthesis and autophagy in primary neurons, which may represent a novel pathway with potential therapeutic value for the treatment of Parkinson's disease. Inhibition of GlcCer synthase enhances autophagy by inhibiting AKT-mTOR signaling, and increases the number and size of lysosomal/late endosomal structures. Furthermore, inhibition of GlcCer synthase decreased levels of mutant α-synuclein in neurons, which may represent a potential therapeutic target for Parkinson's disease. |
| Databáze: | OpenAIRE |
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