P03 - Homeostasis

Neuronal NAADP signalling during neuroinflammation

Neuroinflammation, as observed in multiple sclerosis (MS), is often accompanied by elevated extracellular glutamate levels, leading to excitotoxic neuronal death. A central feature of this excitotoxicity is excessive calcium (Ca²⁺) influx, predominantly through glutamate receptors, disrupting intracellular Ca²⁺ homeostasis. Recent evidence implicates the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) in mediating glutamate-evoked Ca²⁺ signals from acidic organelles, yet the mechanisms of NAADP signaling in neurons and its role in neurodegeneration remain poorly defined.

While NAADP is a potent known Ca²⁺-mobilizing messenger, its dual role in supporting physiological Ca²⁺ oscillations and contributing to excitotoxicity is not understood. The identity of NAADP-forming enzymes and receptor proteins responsible for this bifunctional activity in neurons remains elusive. We aim to disentangle the neuroprotective vs. neurotoxic roles of NAADP signaling during glutamate stimulation, with a long-term goal of identifying therapeutic targets to counteract neurodegeneration in inflammatory CNS diseases.

Using genetically engineered mouse models lacking the NAADP receptors HN1L/JPT2 and LSM12, as well as NAADP-producing enzymes (e.g., CD38, DUOX2, NOX2), we will dissect NAADP’s contribution to synaptic vs. extra-synaptic glutamate signaling. State-of-the-art high- and super-resolution Ca²⁺ imaging in hippocampal neurons will be combined with pharmacological interventions and in vitro models of neuroinflammation. In vivo relevance will be tested using the experimental autoimmune encephalomyelitis (EAE) model of MS.

This project will establish a functional map of NAADP signaling pathways that define whether glutamate stimulation supports neuronal function or triggers excitotoxic death. By identifying specific molecular players in protective vs. pathological Ca²⁺ signaling, we aim to uncover novel targets for therapeutic intervention in neuroinflammatory diseases such as MS, offering a mechanistic foundation for future translational strategies.