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Nat Commun. 2015 Apr 13;6:6768. doi: 10.1038/ncomms7768.

Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain.

Author information

1
Department of Biology, Stanford University, Stanford, California 94305, USA.
2
Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.

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.

PMID:
25866135
PMCID:
PMC4515032
DOI:
10.1038/ncomms7768
[Indexed for MEDLINE]
Free PMC Article

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