The Sanders lab is interested in how neurons use the protein-lipid modification palmitoylation to target proteins to specific subcellular locations in and to define how palmitoylation-dependent targeting contributes to physiological neuronal function and neuropathological conditions. Precise control of neuronal excitability, or whether or not a neuron fires a nerve impulse to its neighbours, is essential for normal behaviour and cognition, while aberrant excitability is a hallmark of many neurological diseases, including epilepsy, bipolar disorder, Schizophrenia, and autism spectrum disorder. The key factor that controls the threshold of excitability is the clustering of ion channels and receptors at sites of excitability, including synapses, axon initial segments (AIS), and nodes of Ranvier; but how such clustering is regulated is not fully understood. Current areas of research in the Sanders lab include:
- How does palmitoylation control voltage-gated sodium and potassium channel targeting and function at the AIS and nodes of Ranvier?
- How do physiological and pathological changes in neuronal activity impact potassium and sodium channel palmitoylation and targeting to the AIS?
- What palmitoyl acyltransferase and palmitoyl protein thioesterase enzymes palmitoylate and depalmitoylate, respectively, sodium and potassium ion channels and how are they regulated by physiological and pathological changes in neuronal activity?
- Do human mutations in ion channels that cause ataxia and seizure disorders alter channel palmitoylation and targeting to sites of excitability?
- How does palmitoylation regulate axonal trafficking of cargo to sites of neuronal excitability?
We use cutting edge genetic, biochemical, and cell biological approaches to answer these questions, including CRISPR-mediated gene knockout and mutation, shRNA-mediated knockdown and rescue, specialized palmitoylation assays, and live and fixed confocal microscopy in neuronal cultures grown in conventional culture and in microfluidic devices.