Phagocytic Glia Are Obligatory Intermediates in Transmission Of
RESEARCH ARTICLE Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses Kirby M Donnelly1, Olivia R DeLorenzo2, Aprem DA Zaya1, Gabrielle E Pisano1, Wint M Thu1, Liqun Luo3,4, Ron R Kopito3, Margaret M Panning Pearce1,2* 1Department of Biological Sciences, University of the Sciences, Philadelphia, United States; 2Program in Neuroscience, University of the Sciences, Philadelphia, United States; 3Department of Biology, Stanford University, Stanford, United States; 4Howard Hughes Medical Institute, Stanford University, Stanford, United States Abstract Emerging evidence supports the hypothesis that pathogenic protein aggregates associated with neurodegenerative diseases spread from cell to cell through the brain in a manner akin to infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult Drosophila olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal activity and blocked by inhibiting caspases in presynaptic neurons, implicating synaptic dysfunction and cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires the glial scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected neurons. These findings expand our understanding
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