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 of phagocytic glia as double-edged players in neurodegeneration—by clearing neurotoxic protein aggregates, but also providing an opportunity for prion-like seeds to evade phagolysosomal degradation and propagate further in the brain.
14Emerging evidence supports the hypothesis that pathogenic protein aggregates associated with 15 many neurodegenerative diseases spread from cell to cell through the brain in a manner akin to 16 infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington 17 disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult Drosophila 18 olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal 19 activity and blocked by caspase inhibition in presynaptic neurons, implicating synaptic dysfunction and 20 cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires 21 the scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that 22 phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected 23 neurons. These findings expand our understanding of phagocytic glia as double-edged players in 24 neurodegeneration-they clear neurotoxic protein aggregates, but also provide opportunities for prion-25 like seeds to evade phagolysosomal degradation and propagate further in the brain. 26 93 5 RESULTS 94Anterograde transfer of prion-like mHtt aggregates across synapses in the adult fly olfactory system 95 Aggregates formed by N-terminal fragments of mHtt generated by aberrant splicing (e.g., exon 96 1; Httex1) (Sathasivam et al., 2013) or caspase cleavage (e.g., exon 1-12; Httex1-12) (Graham et al., 2006) 97 (Fig. 1A) accumulate in HD patient brains, are highly cytotoxic, and spread between cells in culture and 98 in vivo (Babcock and Ganetzky, 2015; Costanzo et al., 2013; Pearce et al., 2015; Pecho-Vrieseling et 99 al., 2014; Ren et al., 2009). We have previously established transgenic Drosophila that employ binary 100 expression systems [e.g., Gal4-UAS, QF-QUAS, or LexA-LexAop (Riabinina and Potter, 2016)] to 101 express fluorescent protein (FP) fusions of Httex1 in non-overlapping cell populations in order to monitor 102 cell-to-cell transfer of mHttex1 aggregates in intact brains (Donnelly and Pearce, 2018; Pearce et al., 103 2015). Our experimental approach (Fig. 1B) exploits the fact that wtHttex1 proteins only aggregate upon 104 encountering mHttex1 aggregate seeds (Chen et al., 2001; Preisinger et al., 1999), such that transfer of 105 mHttex1 aggregates from "donor" cells is reported by conversion of cytoplasmic wtHttex1 from its normally 106 soluble, diffuse state to a punctate, aggregated state in "acceptor" cells. To confirm that mHttex1 107 nucleates the aggregation of wtHttex1 in fly neurons, we co-expressed FP-fusions of these two proteins 108 using pan-neuronal elav[C155]-Gal4. In flies expressing only mCherry-tagged mHttex1 (Httex1Q91-109 mCherry) pan-neuronally, aggregates were visible as discrete mCherry+ puncta throughout neuronal 110 cell bodies and neuropil regions of adult fly brains ( Fig. 1-figure supplement 1A). By contrast, GFP-111 tagged wtHttex1 (Httex1Q25-GFP) was expressed di...
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