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ATP8A2 EXPRESSION CONTROLS NEURONAL STRUCTURAL INTEGRITY AND SURVIVAL THROUGH PHOSPHATIDYLSERINE REGULATION
Adriana Schneiderand 11 co-authors
Heidelberg University
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-223
Presentation
Date TBA
Board: PS05-09AM-223
Event Information
Poster Board
PS05-09AM-223
Poster
View posterAbstract
Phosphatidylserine (PS) asymmetry at the plasma membrane is actively maintained for cellular function, and its loss is traditionally linked to apoptotic signalling in many cell types. PS spatial distribution, regulatory mechanisms, and functional relevance in mature neurons remains poorly understood, particularly in neurodegeneration. We addressed this gap by examining PS dynamics in mature hippocampal neurons under physiological and pathological conditions. Live imaging revealed that PS exposure is not randomly distributed but forms discrete externalization hotspots at dendritic branching points, suggesting an active regulation rather than passive membrane disruption. To identify the underlying mechanism, we combined in vitro and in vivo models of neurodegeneration with molecular modelling, RNA interference, pharmacological perturbation, and biochemical analyses. This approach identified the flippase Atp8a2 as the key regulator of PS asymmetry in mature neurons. Neurotoxic stress and multiple neurodegeneration mouse models consistently showed altered Atp8a2 expression, leading to enhanced PS exposure, compromised dendritic structure, and increased susceptibility to death. Notably, neuronal architecture and viability depended primarily on Atp8a2 expression levels rather than flippase activity alone. In contrast, elevating Atp8a2 expression reduced PS externalization and provided neuroprotection. Together, our findings redefine PS exposure in mature neurons as a regulated and spatially confined process linked to structural integrity and viability. Atp8a2 expression emerges as a critical mechanism that links PS asymmetry to neuronal survival, identifying it as a potential target in neurodegenerative disease.
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