Grant: Project Grant

Neurons are the basic working unit of the brain. They transmit information from other neurons or sensory organs to downstream neurons or muscles and, in doing so, control learning and memory, movement, and other tasks. Neurons are large and complex with long projections, called axons, that send electrical impulses to other neurons they are connected to. Ion channels are a critical group of proteins that mediate neuron electrical impulses. These channels open and close to form pores or small holes in the outer fatty layer of the neuron known as the membrane. They initiate and carry electrical impulses along axons and must be present in specific locations on the axon to ensure normal brain function. Ion channels are extremely important for brain function and multiple human disorders, such as epilepsy and ataxia, are caused by mutations in ion channels that result in the channel not performing its job correctly. These ion channels are normally modified with a sticky tag in a process called palmitoylation. The sticky tag acts like a postal code that helps other cell machinery transport ion channels to the correct location. We hypothesize that palmitoylation directs and retains ion channels at the sites where electrical impulses are generated and that this can be modified to treat epilepsy and ataxia. To test this hypothesis, we will use neurons to determine exactly how the sticky tag directs ion channels to specific sites in the neuron and how that goes wrong in human disorders. We will then use that information to determine if increasing palmitoylation blocks seizures and/or ataxia from developing. This work will provide new insights into the regulation of transport of cellular components in brain cells and a better understanding of their normal function. Our findings will also have important implications for understanding disorders such as epilepsy, where there is too much brain electrical activity.