1. Cell Biology
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Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses

  1. Kirby M Donnelly
  2. Olivia R DeLorenzo
  3. Aprem DA Zaya
  4. Gabrielle E Pisano
  5. Wint M Thu
  6. Liqun Luo
  7. Ron R Kopito
  8. Margaret M Panning Pearce  Is a corresponding author
  1. University of the Sciences, United States
  2. Howard Hughes Medical Institute, Stanford University, United States
  3. Stanford University, United States
Research Article
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Cite this article as: eLife 2020;9:e58499 doi: 10.7554/eLife.58499

Abstract

Emerging evidence supports the hypothesis that pathogenic protein aggregates associated with neurodegenerative diseases spread from cell to cell through the brain in a manner akin to infectious prions. Here, we show that mutant huntingtin (mHtt) aggregates associated with Huntington disease transfer anterogradely from presynaptic to postsynaptic neurons in the adult Drosophila olfactory system. Trans-synaptic transmission of mHtt aggregates is inversely correlated with neuronal activity and blocked by inhibiting caspases in presynaptic neurons, implicating synaptic dysfunction and cell death in aggregate spreading. Remarkably, mHtt aggregate transmission across synapses requires the glial scavenger receptor Draper and involves a transient visit to the glial cytoplasm, indicating that phagocytic glia act as obligatory intermediates in aggregate spreading between synaptically-connected neurons. These findings expand our understanding of phagocytic glia as double-edged players in neurodegeneration—by clearing neurotoxic protein aggregates, but also providing an opportunity for prion-like seeds to evade phagolysosomal degradation and propagate further in the brain.

Article and author information

Author details

  1. Kirby M Donnelly

    Department of Biological Sciences, University of the Sciences, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Olivia R DeLorenzo

    Program in Neuroscience, University of the Sciences, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Aprem DA Zaya

    Department of Biological Sciences, University of the Sciences, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Gabrielle E Pisano

    Department of Biological Sciences, University of the Sciences, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Wint M Thu

    Department of Biological Sciences, University of the Sciences, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Liqun Luo

    Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5467-9264

  7. Ron R Kopito

    Biology, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Margaret M Panning Pearce

    Department of Biological Sciences, Program in Neuroscience, University of the Sciences, Philadelphia, United States
    For correspondence
    m.pearce@usciences.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5846-9632

Funding

Pittsburgh Foundation (Integrated Research & Education Grant,UN2018-98318)

  • Margaret M Panning Pearce

W.W. Smith Charitable Trusts (Research Grant)

  • Margaret M Panning Pearce

National Institutes of Health (R03-AG063295)

  • Margaret M Panning Pearce

National Institutes of Health (R01-DC005982)

  • Liqun Luo

National Institutes of Health (R01-NS042842)

  • Ron R Kopito

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Hugo J Bellen, Baylor College of Medicine, United States

Publication history

  1. Received: May 2, 2020
  2. Accepted: May 22, 2020
  3. Accepted Manuscript published: May 28, 2020 (version 1)
  4. Version of Record published: June 16, 2020 (version 2)

Copyright

© 2020, Donnelly et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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