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Kevin Rhine1,2,3, Elle Epstein1,2,3, Natasha M Carlson4,5

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Mitochondrial-derived double-stranded RNA (dsRNA) activates the integrated stress response (ISR) in aged neurons, contributing to neurodegeneration. Inhibiting PKR kinase restores cellular function and translation.

Keywords:
agingdouble-stranded RNAintegrated stress responsemitochondrianeurodegenerationstress granules

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Area of Science:

  • Neurobiology
  • Cellular Biology
  • Molecular Biology

Background:

  • Neurodegenerative diseases are associated with disruptions in the integrated stress response (ISR).
  • The specific cellular stressors contributing to aging and neurodegeneration remain debated.
  • The ISR is crucial for maintaining cellular homeostasis under stress.

Purpose of the Study:

  • To identify the source of integrated stress response (ISR) activation in aged neurons.
  • To investigate the role of cytoplasmic double-stranded RNA (dsRNA) in ISR activation.
  • To explore PKR kinase as a mediator of ISR in aged neurons.

Main Methods:

  • Directed transdifferentiation of human fibroblasts into aged neurons.
  • Analysis of cytoplasmic dsRNA accumulation and its interaction with PKR.
  • Assessment of mitochondrial integrity and dsRNA leakage.
  • Evaluation of PKR inhibition effects on cellular stress and translation.

Main Results:

  • Increased cytoplasmic dsRNA accumulation activates PKR, triggering the ISR in aged neurons.
  • Mitochondrial-derived dsRNA accumulates in aged neurons, binds to PKR, and leaks into the cytoplasm.
  • PKR activation leads to dsRNA sequestration in stress granules.
  • PKR inhibition reduces cellular stress, restores translation, and normalizes RNA-binding protein expression.

Conclusions:

  • Endogenous mitochondrial dsRNA is a key source of RNA stress in aged neurons.
  • Dysregulated ISR, mediated by PKR and mitochondrial dsRNA, contributes to neuronal destabilization and neurodegeneration.
  • Targeting PKR may offer a therapeutic strategy for neurodegenerative diseases.