title: Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain.
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.
authors: Department of Biology, Stanford University, Stanford, California 94305, USA.
authors: Margaret M P
authors: MMP
authors: Pearce
authors: Department of Biology, Stanford University, Stanford, California 94305, USA.
authors: Ellen J
authors: EJ
authors: Spartz
authors: Department of Biology, Stanford University, Stanford, California 94305, USA.|Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
authors: Weizhe
authors: W
authors: Hong
authors: Department of Biology, Stanford University, Stanford, California 94305, USA.|Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.
authors: Liqun
authors: L
authors: Luo
authors: Department of Biology, Stanford University, Stanford, California 94305, USA.
authors: Ron R
authors: RR
authors: Kopito
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D018716:Molecular Mimicry; D009154:Mutation; D009457:Neuroglia / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D010587:Phagocytosis; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000097573:Red Fluorescent Protein
chemical_list: D001426:Bacterial Proteins; D029721:Drosophila Proteins; D000071058:Huntingtin Protein; D008164:Luminescent Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D011328:Prions; D066329:Protein Aggregates; D000097573:Red Fluorescent Protein; C542005:Htt protein, Drosophila; C495322:drpr protein, Drosophila; C054562:yellow fluorescent protein, Bacteria