Abstract：
: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.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Shen W,Henry AG,Paumier KL,Li L,Mou K,Dunlop J,Berger Z,Hirst WDdoi
10.1111/jnc.12672subject
Has Abstractpub_date
2014-06-01 00:00:00pages
884-94issue
5eissn
0022-3042issn
1471-4159journal_volume
129pub_type
杂志文章abstract：:The present study aims to investigate the role of extracellular glutamate and NMDA receptor stimulation in the neuronal death induced by a transient exposure to H2O2 of cultured neurons originating from mouse cerebral cortex. Most of the neuronal loss following a transient exposure to H2O2 of cortical neurons results ...
journal_title：Journal of neurochemistry
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journal_title：Journal of neurochemistry
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
doi：10.1046/j.1471-4159.2001.00398.x
更新日期：2001-07-01 00:00:00
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journal_title：Journal of neurochemistry
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journal_title：Journal of neurochemistry
pub_type： 杂志文章,评审
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更新日期：2007-12-01 00:00:00
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journal_title：Journal of neurochemistry
pub_type： 杂志文章
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journal_title：Journal of neurochemistry
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更新日期：2008-03-01 00:00:00
abstract：:Acetylcholine is a key neurotransmitter of the inner ear efferent system. In this study, we identify two novel nAChR subunits in the inner ear: α1 and γ, encoded by Chrna1 and Chrng, respectively. In situ hybridization shows that the messages of these two subunits are present in vestibular and cochlear hair cells duri...
journal_title：Journal of neurochemistry
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更新日期：2007-12-01 00:00:00
