New Publications Beyond apoptosis: phosphatidylserine marks structurally weak points in adult neurons

A new study led by Prof. Dr. Daniela Mauceri and colleagues has uncovered a new mechanism linking membrane lipids to structural integrity and survival of mature neurons. The team found that it is the expression level of the membrane protein Atp8a2 — not its enzymatic activity — that determines whether surface phosphatidylserine concentrates at branching points. Loss of Atp8a2 disrupted phosphatidylserine distribution, compromised neuronal architecture and increased vulnerability to degeneration, while increasing Atp8a2 levels provided substantial neuroprotection. The findings were published in the journal Cell Death & Disease.

Cell membranes maintain an asymmetric distribution of phospholipids. One of these, phosphatidylserine, normally sits on the inner, cytoplasmic side and appears on the surface mainly as an apoptotic signal. In neurons though, it can also become transiently exposed during stress, well before neuronal death; a process whose control and relevance to neurodegeneration was previously unknown. Time-lapse imaging showed that phosphatidylserine appears on the surface of mature hippocampal neurons in distinct hotspots concentrated at dendritic branching points and spines. These structures are essential for neuronal connectivity and potentially vulnerable during degeneration. Excitotoxic stimulation intensified this exposure at these key sites and selectively reduced the protein levels of the flippase Atp8a2. A similar decrease in Atp8a2 appeared across several mouse models of neurodegeneration, including excitotoxic retinal damage, seizures and Alzheimer’s disease. Atp8a2 proved essential for structural integrity in mature neurons: reducing its expression increased phosphatidylserine exposure towards dendritic branching points and spines, and caused neurons to lose dendritic length and complexity, signs of early neurodegeneration. In adult mice, reduced Atp8a2 also caused axonal stress and damage in the optic nerve. Atp8a2 may also link membrane organization to the neuronal cytoskeleton, the network supporting dendrites, axons and synapses. Here, Atp8a2 was enriched in compartments associated with synaptic and structural proteins, suggesting a direct role in neuronal architecture.  Further, loss of Atp8a2 triggered neuronal death and left neurons more vulnerable to toxicity. None of these effects could be explained by compromised enzymatic activity alone. Atp8a2 normally acts as a flippase, transporting phosphatidylserine from the outer to the inner membrane layer. Blocking this activity increased exposure, but caused none of the redistribution, structural damage or death seen with loss of the protein itself, pointing to a role beyond lipid transport.  Increasing Atp8a2 expression, conversely, was strongly neuroprotective: neurons kept normal PS distribution under excitotoxic stress and were significantly more resistant to cell death.  Understanding what controls Atp8a2 expression — and how to preserve or boost it — may open new strategies for protecting neurons in stroke, Alzheimer's disease and other neurodegenerative conditions.

The research involved scientists from Heidelberg University, Philipps-Universität Marburg, Marche Polytechnic University, the Mario Negri Institute for Pharmacological Research and the University of Milan.

The work was supported by the German Research Foundation, the Chica and Heinz Schaller Foundation, Alzheimer Forschung Initiative, the Joachim Herz Foundation, the Italian Ministry of University and Research, the Giovanni Armenise Harvard Foundation and AIRALZH ONLUS. 

Source: Schneider, A., Merkel, A. B., Perta, N., Ruff, L., Ussyshkin, N., Zimmer, P., Aksan, B., Lepeuve, A., D'Andrea, L., Pelucchi, S., Marcello, E., Di Marino, D., & Mauceri, D. (2026). Loss of Atp8a2 drives neurodegeneration through the dysregulation of spatiotemporal phosphatidylserine externalization in mature neurons. Cell death & disease, 17(1), 652. https://doi.org/10.1038/s41419-026-09097-y