Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons
Version of Record online: 3 MAR 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 129, Issue 5, pages 884–894, June 2014
How to Cite
J. Neurochem. (2014) 129, 884–894.
- Issue online: 18 MAY 2014
- Version of Record online: 3 MAR 2014
- Accepted manuscript online: 4 FEB 2014 12:42PM EST
- Manuscript Accepted: 29 JAN 2014
- Manuscript Revised: 24 JAN 2014
- Manuscript Received: 16 NOV 2013
- Michael J. Fox Foundation
- Parkinson's disease
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.