Tau-induced deficits in nonsense-mediated mRNA decay contribute to neurodegeneration

Alzheimers Dement. 2023 Feb;19(2):405-420. doi: 10.1002/alz.12653. Epub 2022 Apr 13.


Introduction: While brains of patients with Alzheimer's disease and related tauopathies have evidence of altered RNA processing, we lack a mechanistic understanding of how altered RNA processing arises in these disorders and if such changes are causally linked to neurodegeneration.

Methods: Using Drosophila melanogaster models of tauopathy, we find that overall activity of nonsense-mediated mRNA decay (NMD), a key RNA quality-control mechanism, is reduced. Genetic manipulation of NMD machinery significantly modifies tau-induced neurotoxicity, suggesting that deficits in NMD are causally linked to neurodegeneration. Mechanistically, we find that deficits in NMD are a consequence of aberrant RNA export and RNA accumulation within nuclear envelope invaginations in tauopathy. We identify a pharmacological activator of NMD that suppresses neurodegeneration in tau transgenic Drosophila, indicating that tau-induced deficits in RNA quality control are druggable.

Discussion: Our studies suggest that NMD activators should be explored for their potential therapeutic value to patients with tauopathies.

Keywords: Alzheimer's disease; Drosophila; neurodegeneration; nonsense-mediated mRNA decay; nucleus; tauopathy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Drosophila / genetics
  • Drosophila melanogaster / genetics
  • Nonsense Mediated mRNA Decay*
  • RNA
  • Tauopathies* / genetics


  • RNA