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

Nat Commun. 2015 Apr 13;6:6768. doi: 10.1038/ncomms7768.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Disease Progression
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics
  • Huntington Disease / metabolism
  • Huntington Disease / pathology*
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Molecular Mimicry
  • Mutation
  • Neuroglia / chemistry
  • Neuroglia / metabolism*
  • Neuroglia / pathology
  • Neurons / chemistry
  • Neurons / metabolism*
  • Neurons / pathology
  • Phagocytosis
  • Prions / chemistry
  • Prions / metabolism
  • Protein Aggregates
  • Protein Aggregation, Pathological / genetics*
  • Protein Aggregation, Pathological / metabolism
  • Signal Transduction

Substances

  • Bacterial Proteins
  • Drosophila Proteins
  • Htt protein, Drosophila
  • Huntingtin Protein
  • Luminescent Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Prions
  • Protein Aggregates
  • drpr protein, Drosophila
  • red fluorescent protein
  • yellow fluorescent protein, Bacteria