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Updated: Nov 7, 2025
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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.
Summary
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.
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