Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses
- University of the Sciences, United States
- Howard Hughes Medical Institute, Stanford University, United States
- Stanford University, United States
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
Margaret M Panning Pearce
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.
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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Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses
eLife 9:e58499.
https://doi.org/10.7554/eLife.58499
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