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HERO ID
2284073
Reference Type
Journal Article
Title
Motor neuropathy-associated mutation impairs Seipin functions in neurotransmission
Author(s)
Wei, S; Soh, SL; Xia, J; Ong, WY; Pang, ZP; Han, W
Year
2014
Is Peer Reviewed?
Yes
Journal
Journal of Neurochemistry
ISSN:
0022-3042
EISSN:
1471-4159
Volume
129
Issue
2
Page Numbers
328-338
Language
English
PMID
24345054
DOI
10.1111/jnc.12638
Abstract
Gain-of-toxic-function mutations in Seipin (Asparagine 88 to Serine (N88S) and Serine 90 to Leucine (S90L) mutations, both of which disrupt the N-glycosylation) cause autosomal dominant motor neuron diseases. However, the mechanism of how these missense mutations lead to motor neuropathy is unclear. Here, we analyze the impact of disruption of N-glycosylation of Seipin on synaptic transmission by over-expressing mutant Seipin in cultured cortical neurons via lentiviral infection. Immunostaining shows that over-expressed Seipin is partly colocalized with synaptic vesicle marker synaptophysin. Electrophysiological recordings reveal that the Seipin mutation significantly decreases the frequency, but not the amplitudes of miniature excitatory post-synaptic currents and miniature inhibitory post-synaptic currents. The amplitude of both evoked excitatory post-synaptic currents and inhibitory post-synaptic current is also compromised by mutant Seipin over-expression. The readily releasable pool and vesicular release probability of synaptic vesicles are both altered in neurons over-expressing Seipin-N88S, whereas neither γ-amino butyric acid (GABA) nor α-Amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) induced whole cell currents are affected. Moreover, electron microscopy analysis reveals decreased number of morphologically docked synaptic vesicles in Seipin-N88S-expressing neurons. These data demonstrate that Seipin-N88S mutation impairs synaptic neurotransmission, possibly by regulating the priming and docking of synaptic vesicles at the synapse. Motoneuropathy-associated endoplasmic reticulum (ER) protein Seipin-N88S mutation disrupts N-glycosylation and decreased the frequency of miniature excitatory and inhibitory post-synaptic currents (PSCs), and the amplitude of evoked excitatory and inhibitory PSCs. The readily releasable pool and synaptic vesicle (SV) release probability were reduced in neurons over-expressing Seipin-N88S, along with decreased number of docked vesicles. We propose that Seipin-N88S mutation impairs synaptic neurotransmission by regulating the docking of synaptic vesicles.
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n-Butanol
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Pubmed
Database Searches - March 2014 (private)
Pubmed - 3/2014
Excluded (not pertinent)
Not chemical specific
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