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Citation
Donnelly, K.M., DeLorenzo, O.R., Zaya, A.D., Pisano, G.E., Thu, W.M., Luo, L., Kopito, R.R., Panning Pearce, M.M. (2020). Phagocytic glia are obligatory intermediates in transmission of mutant huntingtin aggregates across neuronal synapses.  eLife 9(): e58499.
FlyBase ID
FBrf0245970
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC7297539 (PMC) (EuropePMC)
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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    eLife
    Title
    eLife
    ISBN/ISSN
    2050-084X
    Data From Reference
    Alleles (31)
    Genes (13)
    Human Disease Models (1)
    Natural transposons (1)
    Insertions (5)
    Experimental Tools (8)
    Transgenic Constructs (25)