Abstract
The brain has a limited capacity to self-protect against protein aggregate-associated pathology, and mounting evidence supports a role for phagocytic glia in this process. We have established a Drosophila model to investigate the role of phagocytic glia in clearance of neuronal mutant huntingtin (Htt) aggregates associated with Huntington disease. We find that glia regulate steady-state numbers of Htt aggregates expressed in neurons through a clearance mechanism that requires the glial scavenger receptor Draper and downstream phagocytic machinery. Remarkably, some of these engulfed neuronal Htt aggregates effect prion-like conversion of soluble, wild-type Htt in the glial cytoplasm. We provide genetic evidence that this conversion depends strictly on the Draper signaling pathway, unveiling a previously unanticipated role for phagocytosis in transfer of pathogenic protein aggregates in an intact brain. These results suggest a potential mechanism by which phagocytic glia contribute to both protein aggregate-related neuroprotection and pathogenesis in neurodegenerative disease.
Highlights
The brain has a limited capacity to self-protect against protein aggregate-associated pathology, and mounting evidence supports a role for phagocytic glia in this process
Confocal microscopy indicated that HttQ91 expressed in DA1 Olfactory receptor neurons (ORNs) was restricted to discrete puncta that were in close proximity to a coexpressed membrane marker, mCD8-green fluorescent protein (GFP), reflecting the high aggregation propensity of this mutant Htt exon 1 fusion protein (Fig. 1b)
HttQ91 puncta were largely concentrated in the ORN axon terminals in the DA1 glomerulus, where these ORNs synapse with dendrites of projection neurons, and some puncta could be observed in the DA1 ORN axon bundles along the dorsal surface of the antennal lobe (Fig. 1c)
Summary
The brain has a limited capacity to self-protect against protein aggregate-associated pathology, and mounting evidence supports a role for phagocytic glia in this process. We provide genetic evidence that this conversion depends strictly on the Draper signalling pathway, unveiling a previously unanticipated role for phagocytosis in transfer of pathogenic protein aggregates in an intact brain These results suggest a potential mechanism by which phagocytic glia contribute to both protein aggregate-related neuroprotection and pathogenesis in neurodegenerative disease. A growing body of evidence supports the hypothesis that physical movement of ordered, fibrillar protein aggregates between cells in the CNS contributes to this propagation by recruiting nonaggregated conformers of the same protein in a process akin to the spread of aggregated PrPSc in transmissible spongiform encephalopathies and related prion disorders[4] While both in vitro cell culture studies[5,6,7,8,9,10,11,12,13,14] and in vivo mouse models[11,15,16,17,18,19,20] provide mounting support for a role for prion-like mechanisms in non-cell-autonomous spreading of neurodegenerative diseases, almost nothing is known about the mechanisms by which these agents physically move from one cell to another. These findings suggest that phagocytic clearance of neuronal Htt protein aggregates by glia might contribute to the spread of pathogenic protein aggregates in neurodegenerative disease
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