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Updated: Jun 22, 2025

In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
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Pathogenic tau induces an adaptive elevation in mRNA translation rate at early stages of disease

Gabrielle Zuniga1,2,3, Sakie Katsumura1,4,5, Jasmine De Mange1,2,3

  • 1Barshop Institute for Longevity and Aging Studies, San Antonio, Texas, USA.

Aging Cell
|June 27, 2024
PubMed

Insights

In tauopathy, elevated mRNA translation and peptide accumulation occur early. Activating RNA surveillance mechanisms like NMD may be an adaptive response to limit neurodegeneration.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Alterations in messenger RNA (mRNA) translation rates and accuracy are linked to aging and neurodegenerative diseases like Alzheimer's.
  • Nonsense-mediated mRNA decay (NMD) is a crucial RNA surveillance pathway that clears error-containing RNA.
  • Previous work showed that error-containing RNA are translated in a Drosophila model of tauopathy.

Purpose of the Study:

  • To investigate the impact of tau pathology on mRNA translation and related cellular processes in the brain.
  • To determine if elevated translation rates are an adaptive mechanism in early tauopathy.
  • To explore the relationship between NMD, translation, and neurodegeneration.

Main Methods:

  • Utilized Drosophila models of tauopathy.
  • Analyzed peptide and translation machinery accumulation in nuclear envelope invaginations.
  • Performed polysome profiling to assess global and specific mRNA translation rates.
  • Investigated the effects of panneuronal NMD elevation and rapamycin treatment on translation and neurodegeneration.

Main Results:

  • Tau pathology leads to the accumulation of newly-synthesized peptides and translation machinery within nuclear envelope invaginations.
  • Global mRNA translation rates are elevated in the early stages of tauopathy in Drosophila brains.
  • Specific mRNAs previously linked to neurodegeneration are preferentially translated.
  • Panneuronal NMD elevation and rapamycin treatment paradoxically increase global translation rates in tau transgenic flies.
  • Both NMD activation and rapamycin treatment were found to suppress tau-induced neurodegeneration.

Conclusions:

  • Elevated mRNA translation rates appear to be an early adaptive mechanism to mitigate neurodegeneration in tauopathy.
  • Tau-induced deficits in NMD contribute to altered mRNA translation, increasing the translation of normally repressed RNAs.
  • These findings highlight a complex interplay between RNA surveillance, translation, and neuroprotection in tauopathies.
Keywords:
DrosophilaAlzheimer's diseaseneurodegenerationnonsense‐mediated mRNA decaynucleusprotein translationtauopathy

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