1. Cell Biology
  2. Neuroscience
Download icon

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
  • Cited 3
  • Views 2,040
  • Annotations
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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

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.

Metrics

  • 2,040
    Page views
  • 319
    Downloads
  • 3
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Aixin Song et al.
    Research Article Updated

    UCH37, also known as UCHL5, is a highly conserved deubiquitinating enzyme (DUB) that associates with the 26S proteasome. Recently, it was reported that UCH37 activity is stimulated by branched ubiquitin (Ub) chain architectures. To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and Nuclear Magnetic Resonance (NMR) structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal Ubs that emanate from a branched Ub. In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear Ub chains from having access to the UCH37 active site. In cultured human cells under conditions of proteolytic stress, we show that substrate clearance by the proteasome is promoted by both binding and deubiquitination of branched polyubiquitin by UCH37. Proteasomes containing UCH37(C88A), which is catalytically inactive, aberrantly retain polyubiquitinated species as well as the RAD23B substrate shuttle factor, suggesting a defect in recycling of the proteasome for the next round of substrate processing. These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique Ub chain architecture is aided by a DUB.

    1. Cell Biology
    2. Neuroscience
    Domenica Ippolito et al.
    Research Article Updated

    Sensory and behavioral plasticity are essential for animals to thrive in changing environments. As key effectors of intracellular calcium signaling, Ca2+/calmodulin-dependent protein kinases (CaMKs) can bridge neural activation with the many regulatory processes needed to orchestrate sensory adaptation, including by relaying signals to the nucleus. Here, we elucidate the molecular mechanism controlling the cell activation-dependent nuclear translocation of CMK-1, the Caenorhabditis elegans ortholog of mammalian CaMKI/IV, in thermosensory neurons in vivo. We show that an intracellular Ca2+ concentration elevation is necessary and sufficient to favor CMK-1 nuclear import. The binding of Ca2+/CaM to CMK-1 increases its affinity for IMA-3 importin, causing a redistribution with a relatively slow kinetics, matching the timescale of sensory adaptation. Furthermore, we show that this mechanism enables the encoding of opposite nuclear signals in neuron types with opposite calcium-responses and that it is essential for experience-dependent behavioral plasticity and gene transcription control in vivo. Since CaMKI/IV are conserved regulators of adaptable behaviors, similar mechanisms could exist in other organisms and for other sensory modalities.