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 engulfment 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 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Proteins / genetics
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Bacterial Proteins / metabolism
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Brain / metabolism
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Brain / pathology
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Disease Models, Animal
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Disease Progression
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Drosophila Proteins / genetics*
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Drosophila Proteins / metabolism
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Drosophila melanogaster / genetics*
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Drosophila melanogaster / metabolism
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Gene Expression Regulation
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Genes, Reporter
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Humans
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Huntingtin Protein
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Huntington Disease / genetics
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Huntington Disease / metabolism
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Huntington Disease / pathology*
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Microtubule-Associated Proteins / genetics*
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Microtubule-Associated Proteins / metabolism
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Molecular Mimicry
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Mutation
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Neuroglia / chemistry
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Neuroglia / metabolism*
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Neuroglia / pathology
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Neurons / chemistry
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Neurons / metabolism*
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Neurons / pathology
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Phagocytosis
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Prions / chemistry
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Prions / metabolism
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Protein Aggregates
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Protein Aggregation, Pathological / genetics*
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Protein Aggregation, Pathological / metabolism
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Red Fluorescent Protein
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Signal Transduction
Substances
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Bacterial Proteins
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Drosophila Proteins
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Htt protein, Drosophila
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Huntingtin Protein
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Luminescent Proteins
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Membrane Proteins
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Microtubule-Associated Proteins
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Prions
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Protein Aggregates
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drpr protein, Drosophila
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yellow fluorescent protein, Bacteria