Modulation of phosphatidylserine externalization and its effects on morphology, viability and survival in neurons.

• Applicant: Professorin Dr. Daniela Mauceri
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 435073479

The plasma membrane of eukaryotic cells is characterized by an asymmetrical distribution of lipids. In particular, phosphatidylserine (PS) is typically confined into the inner leaflet. PS exposure on the cell surface has been reported for different cells and linked to apoptosis as it can serve as an "eat me" signal for the removal of dying cells. In neurons, although PS externalization has been observed, its role in neuronal functions and viability is unclear. Further, neuronal PS surface display can be transient. Such transient PS exposure takes place in stressed yet still viable neurons, can get recognized by microglia and triggers phagocytosis. Interference with PS-triggered phagocytosis of neurons has therefore been suggested to be beneficial in disorders of the nervous system. Excitotoxicity is a pathological phenomenon in which an excess of calcium influx leads to neuronal damage and death. Our recent unpublished work showed that excitotoxicity triggers neuronal PS exposure and in vitro and in vivo down-regulation of Atp8a2, an enzyme responsible for the inward movement of PS. We found that reducing Atp8a2 expression in neurons is sufficient to promote PS exposure, impair neuronal structure and greatly affect neuronal viability. Here, we propose to characterize the spatiotemporal dynamics of Atp8a2-mediated PS exposure on the surface of cultured neurons. We will investigate the role of Atp8a2 in the regulation of dendritic and synaptic morphology in neurons of the hippocampus and retina. Finally, using different models to elicit excitotoxicity in vitro and in vivo, we will explore the impact of Atp8a2 in neuronal survival and test its neuroprotective capacities.

• DFG Programme: Research Grants