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Adaptation and sensitization to proteotoxic stress.

Rehana K Leak1

  • 1Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University.

Dose-Response : a Publication of International Hormesis Society
|March 25, 2014
PubMed
Summary

Mild stress can protect cells, but severe stress can harm them. This study shows that even severe proteotoxic stress can lead to cell adaptation, potentially explaining the slow progression of neurodegenerative diseases.

Keywords:
Alzheimer’s diseaseParkinson’s diseaseU-shapeddual hithormesispreconditioningtwo hit

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Area of Science:

  • Neurobiology
  • Cellular Stress Response

Background:

  • Severe stress can cause toxicity, while mild stress often induces adaptations.
  • Neurodegenerative diseases involve complex stress responses.
  • Proteotoxic stress impacts cellular health and disease progression.

Purpose of the Study:

  • To review stress-induced adaptations versus sensitization in neurodegenerative disease models.
  • To investigate if high-dose proteotoxic stress can induce protection in astrocytes.
  • To explore the role of glutathione in stress adaptation and sensitization.

Main Methods:

  • Review of existing literature on stress responses in neurodegeneration.
  • Experimental models of chronic and acute proteotoxic stress using proteasome inhibition.
  • Analysis of cellular responses, including protein upregulation and glutathione levels.
  • Assessment of astrocyte resilience following severe proteotoxic stress.

Main Results:

  • Low-dose chronic proteotoxic stress elicited protection dependent on superoxide dismutase.
  • High-dose acute proteotoxic stress sensitized cells via glutathione depletion.
  • Astrocytes surviving severe proteotoxicity exhibited enhanced resistance, dependent on glutathione.
  • Severe proteotoxicity upregulated several defensive proteins, even when causing sensitization.

Conclusions:

  • Proteotoxic stress can induce adaptive protection or sensitization depending on dose and duration.
  • Glutathione plays a critical role in both stress sensitization and adaptation.
  • Cellular resilience mechanisms, like those in astrocytes, may contribute to the delayed onset of neurodegenerative diseases.
  • Understanding these stress responses could reveal therapeutic targets for neurodegeneration.