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Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation

Hsiang-Yu Chang1, Shin-Chen Hou, Tzong-Der Way

  • 11] Garage Brain Science, Taichung 413, Taiwan [2] Department of Biological Science and Technology, College of Life Sciences, China Medical University, Taichung 404, Taiwan.

Nature Communications
|November 14, 2013
PubMed

Insights

Reactive oxygen species (ROS) trigger TDP-43 protein aggregation in neurodegenerative diseases. Inhibiting heat-shock protein 90 (HSP-90) reduces toxic TDP-43 buildup, suggesting a common disease mechanism.

Area of Science:

  • Neurobiology
  • Molecular Biology
  • Protein Chemistry

Background:

  • Conformational disorders underlie neurodegenerative diseases.
  • Reactive oxygen species (ROS) are key contributors to neurodegeneration.
  • The precise role of ROS in altering misfolded protein structures remains unclear.

Purpose of the Study:

  • To investigate how ROS influence the aggregation of TDP-43.
  • To explore the mechanism by which ROS induce TDP-43 structural changes.
  • To determine the potential of targeting heat-shock proteins (HSPs) in managing ROS-induced proteinopathies.

Main Methods:

  • Studying TDP-43 aggregation in response to ROS.
  • Analyzing TDP-43 oligomer formation and stress granule assembly.
  • Utilizing HSP-90 inhibitor 17-AAG to assess its effect on TDP-43 pathology.
  • Examining the correlation between ROS-induced TDP-43 assembly and chaperone dynamics.

Main Results:

  • TDP-43's intrinsic aggregation propensity drives assembly of stress granules and toxic oligomers upon ROS insult, independent of disulfide crosslinking.
  • ROS-induced TDP-43 assembly correlates with the dynamics of associated chaperones.
  • HSP-90 inhibition with 17-AAG mitigates ROS-induced TDP-43 aggregation, modifies multimer types, and lessens pathological inclusion severity.

Conclusions:

  • A common pathogenic mechanism involving HSP dysregulation may underlie various conformational diseases.
  • Targeting HSPs offers a potential therapeutic strategy for neurodegenerative conditions involving ROS-induced protein misfolding.

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