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Analyzing Protein Dynamics Using Hydrogen Exchange Mass Spectrometry
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Analyzing Protein Dynamics Using Hydrogen Exchange Mass Spectrometry

Published on: November 29, 2013

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Hsp90 and its co-chaperone Sti1 control TDP-43 misfolding and toxicity

Lilian Tsai-Wei Lin1, Abdul Razzaq2, Sonja E Di Gregorio1

  • 1Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|April 28, 2021
PubMed

Insights

Heat shock protein 90 (Hsp90) and its co-chaperone Sti1 modulate the toxicity of misfolded TDP-43 protein, a key factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS). Impaired Hsp90 function increases TDP-43 toxicity.

Area of Science:

  • Neurobiology
  • Molecular Biology
  • Cell Biology

Background:

  • Protein misfolding is implicated in neurodegenerative diseases.
  • Molecular chaperones can influence protein misfolding toxicity.
  • The specific chaperones interacting with misfolded TDP-43 are not well understood.

Purpose of the Study:

  • To investigate the role of Hsp90 and its co-chaperone Sti1 in TDP-43 misfolding and toxicity.
  • To determine if Hsp90 and Sti1 interact with TDP-43 and modulate its cellular effects.

Main Methods:

  • Experiments were conducted using yeast and mammalian neuronal cell models.
  • Assessed the impact of Hsp90 and Sti1 on TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity.

Main Results:

  • Hsp90 and Sti1 were found to alter TDP-43 misfolding, inclusion formation, aggregation, and cellular toxicity.
  • Impaired Hsp90 function sensitized cells to TDP-43 toxicity.
  • Sti1 specifically interacted with TDP-43 and modulated its toxicity in a dose-dependent manner.

Conclusions:

  • Hsp90 and Sti1 play a significant role in modulating TDP-43 misfolding and associated cellular toxicity.
  • This study reveals a novel connection between the Hsp90 chaperone machinery and TDP-43 pathology in neurodegenerative diseases.
Keywords:
ALSHsp90Sti1TDP-43protein aggregationyeast

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