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

Margaret M. P. Pearce, Ellen J. Spartz, Weizhe Hong, Liqun Luo and Ron R. Kopito ()
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Margaret M. P. Pearce: Stanford University
Ellen J. Spartz: Stanford University
Weizhe Hong: Stanford University
Liqun Luo: Stanford University
Ron R. Kopito: Stanford University

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7768

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