FIXNALCN · Exploring neuronal functions of NALCN in health and disease

The resting membrane potential of a cell is a crucial element of signal transduction across cell membranes and temporary changes are the basis of neuronal excitability. The key ions in the process are unequally distributed intra- and extracellularly and ion channels are regulating the transport. One of the main ions involved in this process are sodium ions. The depolarizing sodium influx on the resting membrane potential is primarily mediated by the sodium leak channel (NALCN). The neurological syndromes IHPRF1 and CLIFAHDD originate from NALCN gain-of-function (GOF) and loss-of-function (LOF) mutations, yet patients have overlapping or highly similar symptoms. Therefore, a genotype-phenotype correlation for these symptoms remains unclear. Here, we aim to understand genotype-phenotype correlations by establishing GOF and LOF patient mutations in a human induced pluripotent stem cell system and characterizing these mutants’ impact on neurological activities and comparing these to the wild type. To further expand our understanding of the patient mutations, I will use computational approaches, such as molecular dynamics to characterize NALCN wt compared to the above NALCN missense mutations. Together with the already available clinical data and the data obtained by the Pless lab in heterologous expression systems, this will provide the first comprehensive overview over the detrimental effects of NALCN GOF and LOF mutations. To date, no negative or positive NALCN modulators have been found or developed to fix patient GOF or LOF mutations, respectively. We aim to identify NALCN modulators using both, in silico docking and in vitro TEVC and patch clamp screening approaches, to treat these neurological phenotypes pharmacologically and thus potential drugs to rectify the effects of NALCN dysfunctions, potentially serving as drug therapy for patients suffering from CLIFAHDD and IHPRF.