Menu
MapConnectionsTopicsBulgariaThe Night (K-TRIO)Marie Skłodowska-CurieFor studentsFor teachersMethodologySurprise me
HEIndividual fellowship2023–2025

FIXNALCN · Exploring neuronal functions of NALCN in health and disease

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2023-07-01 → 2025-06-30
EU contribution
€214,934
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

Lines connect the coordinator with its partners.

Results in brief

Exploring neuronal functions of NALCN in health and disease

Every living cell relies on a tiny electrical gradient across its membrane to function. This gradient, known as the resting membrane potential, regulates essential processes, such as communication between neurons, muscle contraction, cell growth, and even breathing. One of the key players in maintaining the membrane potential is NALCN, a sodium leak channel that helps maintain the delicate balance of ions across the cell membrane. When NALCN does not work properly, children develop rare but severe neurological disorders, including developmental delay, low muscle tone, and breathing irregularities. Interestingly, both gain-of-function (GOF, overactive channel) and loss-of-function (LOF, underactive channel) mutations in NALCN lead to very similar symptoms, despite their opposite effects on the channel itself. This makes it extremely difficult to understand the disease mechanism and to design effective treatments, which are currently not available for patients. The overall aim of this project was to understand how patient variants in the sodium leak channel NALCN alter neuronal activity and to explore ways to correct these defects. First, we generated human stem cell models carrying both GOF and LOF NALCN variants. We then studied how these changes affected the electrical properties and communication of neurons. In the near future, we will we test newly developed compounds designed to restore normal NALCN function, laying groundwork for future therapeutic strategies.

Data: CORDIS, © European Union

Project objective

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.

Original text from CORDIS.

Participants

  • KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark

Links

Data: CORDIS, © European Union