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

Author

Listed:
  • Margaret M. P. Pearce

    (Stanford University)

  • Ellen J. Spartz

    (Stanford University)

  • Weizhe Hong

    (Stanford University
    Howard Hughes Medical Institute, Stanford University
    Present address: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.)

  • Liqun Luo

    (Stanford University
    Howard Hughes Medical Institute, Stanford University)

  • Ron R. Kopito

    (Stanford University)

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.

Suggested Citation

  • Margaret M. P. Pearce & Ellen J. Spartz & Weizhe Hong & Liqun Luo & Ron R. Kopito, 2015. "Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7768
    DOI: 10.1038/ncomms7768
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