Publication Date
9-27-2017
Document Type
Article
Organizational Units
College of Natural Science and Mathematics, Biological Sciences
Keywords
Synaptotagmin, Drosophila, Synaptic proteins, Neuropathy
Abstract
During chemical transmission, the function of synaptic proteins must be coordinated to efficiently release neurotransmitter. Synaptotagmin 2, the Ca2+ sensor for fast, synchronized neurotransmitter release at the human neuromuscular junction, has recently been implicated in a dominantly inherited congenital myasthenic syndrome associated with a non-progressive motor neuropathy. In one family, a proline residue within the C2B Ca2+-binding pocket of synaptotagmin is replaced by a leucine. The functional significance of this residue has not been investigated previously. Here we show that in silico modeling predicts disruption of the C2B Ca2+-binding pocket, and we examine the in vivo effects of the homologous mutation in Drosophila. When expressed in the absence of native synaptotagmin, this mutation is lethal, demonstrating for the first time that this residue plays a critical role in synaptotagmin function. To achieve expression similar to human patients, the mutation is expressed in flies carrying one copy of the wild type synaptotagmin gene. We now show that Drosophila carrying this mutation developed neurological and behavioral manifestations similar to those of human patients and provide insight into the mechanisms underlying these deficits. Our Drosophila studies support a role for this synaptotagmin point mutation in disease etiology.
Copyright Date
9-27-2017
Copyright Statement / License for Reuse
This work is licensed under a Creative Commons Attribution 4.0 International License.
Rights Holder
The Authors
Provenance
Received from author
File Format
application/pdf
Language
English (eng)
Extent
25 pgs
File Size
13552 KB
Publication Statement
Copyright held by the authors. User is responsible for all copyright compliance. This article was originally published as:
Shields, M. C., Bowers, M. R., Fulcer, M. M., Bollig, M. K., Rock, P. J., Sutton, B. R., ..., & Reist, N. E. (2017). Drosophila studies support a role for a presynaptic synaptotagmin mutation in a human congenital myasthenic syndrome. PloS One, 12(9), 1-25. DOI: 10.1371/journal.pone.0184817
Publication Title
PLOS One
Volume
12
Issue
9
First Page
1
Last Page
25
ISSN
1932-6203
Recommended Citation
Shields, M. C., Bowers, M. R., Fulcer, M. M., Bollig, M. K., Rock, P. J., Sutton, B. R., ..., & Reist, N. E. (2017). Drosophila studies support a role for a presynaptic synaptotagmin mutation in a human congenital myasthenic syndrome. PloS One, 12(9), 1-25. DOI: 10.1371/journal.pone.0184817