The phosphatidylserine-binding proteins Turandots protect the peripheral nervous system from antimicrobial peptide toxicity

Inflammation increases with aging and contributes to neurodegeneration, yet the principles that determine how immune effectors target host neural tissue remain poorly understood. Antimicrobial peptides (AMPs) are central components of innate immune defenses strongly induced upon infection and upon aging. Studies have shown that AMPs can exhibit cytotoxicity toward host cells, pointing to a role in neurodegeneration. We show that cationic AMPs selectively bind and damage motoneurons that expose phosphatidylserine (PS), an anionic phospholipid normally restricted to the inner leaflet of the plasma membrane. Both infection and aging increase neuronal PS exposure alongside AMP expression. AMP binding occurs in a PS-dependent manner, leading to synaptic bouton fragmentation, accelerated neuronal aging, and locomotor decline. This toxicity is prevented in Drosophila by Turandot proteins, which reduce AMP-PS interactions on motoneurons. Together, our findings define a molecular mechanism underlying neuronal susceptibility to immunopathology and a set of proteins with neuroprotective potential. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=179 HEIGHT=200 SRC="FIGDIR/small/721952v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@ca817aorg.highwire.dtl.DTLVardef@fa8cb0org.highwire.dtl.DTLVardef@12a8bd4org.highwire.dtl.DTLVardef@423907_HPS_FORMAT_FIGEXP M_FIG This study shows that infection or dysbiosis in Drosophila can simultaneously induce antimicrobial peptide expression while promoting phosphatidylserine (PS) exposure on neurons at the neuromuscular junction. Cationic antimicrobial peptides contribute to neurodegeneration by binding to neurons that expose negatively charged phospholipids such as PS. In Drosophila, a family of secreted peptides, the Turandot proteins, can protect the peripheral nervous system by binding to PS-exposed membranes. Together, these findings reveal a role for antimicrobial peptides, a key component of innate immunity, in promoting neurodegeneration as well as a potential protective mechanism by PS masking agent. C_FIG