| Description |
The SNAP-25 portion of the SNARE (Soluble NSF Attachment Protein REceptor) complex binds to synaptotagmin-1 (snt-1), a calcium ion sensing protein, to facilitate synaptic vesicle fusion and neurotransmitter release. Researchers have identified mutations to specific regions of SNAP-25 and snt-1 that cause neurological disorders, including epilepsy and intellectual disability, in human patients. The exact mechanisms of disease in these patients are unknown. We hypothesized some of these mutations disrupt the primary binding interface between SNAP-25 and snt-1. Here, we used CRISPR/Cas9 to develop disease models in C. elegans, and we used these models to determine how each mutation changes the rates of neurotransmission. We identified a hydrophobic region where mutations resulted in increased rates of neurotransmitter release, as well as a hydrophilic region where mutations resulted in decreased rates of neurotransmitter release. We postulated that snt-1 binds at these regions to perform repressive and stimulating roles, respectively. These findings will help physicians make more informed decisions regarding patient therapies that target increased or decreased rates of neurotransmission. Furthermore, the findings presented here increase the basic science understanding of synaptotagmin-1, its interactions with SNAP-25, and mechanisms by which these mutations cause disease. |
