Tau-Induced Elevation of the Activity-Regulated Cytoskeleton Associated Protein Arc1 Causally Mediates Neurodegeneration in the Adult Drosophila Brain

Lulu Schulz, Paulino Ramirez, Adrienne Lemieux, Elias Gonzalez, Travis Thomson, Bess Frost

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease and other tauopathies are neurodegenerative disorders pathologically defined by aggregated forms of tau protein in the brain. While synaptic degradation is a well-established feature of tau-induced neurotoxicity, the underlying mechanisms of how pathogenic forms of tau drive synaptic dysfunction are incompletely understood. Synaptic function and subsequent memory consolidation are dependent upon synaptic plasticity, the ability of synapses to adjust their structure and strength in response to changes in activity. The activity regulated cytoskeleton associated protein ARC acts in the nucleus and at postsynaptic densities to regulate various forms of synaptic plasticity. ARC harbors a retrovirus-like Gag domain that facilitates ARC multimerization and capsid formation. Trans-synaptic transfer of RNA-containing ARC capsids is required for synaptic plasticity. While ARC is elevated in brains of patients with Alzheimer's disease and genetic variants in ARC increase susceptibility to Alzheimer's disease, mechanistic insight into the role of ARC in Alzheimer's disease is lacking. Using a Drosophila model of tauopathy, we find that pathogenic tau significantly increases multimeric species of the protein encoded by the Drosophila homolog of ARC, Arc1, in the adult fly brain. We find that Arc1 is elevated within nuclei and the neuropil of tau transgenic Drosophila, but does not localize to synaptic vesicles or presynaptic terminals. Lastly, we find that genetic manipulation of Arc1 modifies tau-induced neurotoxicity, suggesting that tau-induced Arc1 elevation mediates neurodegeneration. Taken together, our results suggest that ARC elevation in human Alzheimer's disease is a consequence of tau pathology and is a causal factor contributing to neuronal death.

Original languageEnglish (US)
JournalNeuroscience
DOIs
StateAccepted/In press - 2022

Keywords

  • Alzheimer's disease
  • ARC
  • Drosophila
  • synaptic plasticity
  • tauopathy

ASJC Scopus subject areas

  • Neuroscience(all)

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