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Updated: May 26, 2026
Isolating Potentiated Hsp104 Variants Using Yeast Proteinopathy Models
Published on: November 11, 2014
Different 8-hydroxyquinolines protect models of TDP-43 protein, α-synuclein, and polyglutamine proteotoxicity through
Daniel F Tardiff1, Michelle L Tucci, Kim A Caldwell
1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Abstract:
No current therapies target the underlying cellular pathologies of age-related neurodegenerative diseases. Model organisms provide a platform for discovering compounds that protect against the toxic, misfolded proteins that initiate these diseases. One such protein, TDP-43, is implicated in multiple neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In yeast, TDP-43 expression is toxic, and genetic modifiers first discovered in yeast have proven to modulate TDP-43 toxicity in both neurons and humans. Here, we describe a phenotypic screen for small molecules that reverse TDP-43 toxicity in yeast. One group of hit compounds was 8-hydroxyquinolines (8-OHQ), a class of clinically relevant bioactive metal chelators related to clioquinol. Surprisingly, in otherwise wild-type yeast cells, different 8-OHQs had selectivity for rescuing the distinct toxicities caused by the expression of TDP-43, α-synuclein, or polyglutamine proteins. In fact, each 8-OHQ synergized with the other, clearly establishing that they function in different ways. Comparative growth and molecular analyses also revealed that 8-OHQs have distinct metal chelation and ionophore activities. The diverse bioactivity of 8-OHQs indicates that altering different aspects of metal homeostasis and/or metalloprotein activity elicits distinct protective mechanisms against several neurotoxic proteins. Indeed, phase II clinical trials of an 8-OHQ has produced encouraging results in modifying Alzheimer disease. Our unbiased identification of 8-OHQs in a yeast TDP-43 toxicity model suggests that tailoring 8-OHQ activity to a particular neurodegenerative disease may be a viable therapeutic strategy.
Insights
Researchers screened for compounds to combat toxic proteins like TDP-43, common in neurodegenerative diseases. They discovered 8-hydroxyquinolines (8-OHQ) show promise in yeast models, offering a potential new therapeutic strategy.
Area of Science:
- Neuroscience
- Biochemistry
- Drug Discovery
Background:
- Age-related neurodegenerative diseases lack targeted therapies for underlying cellular pathologies.
- Toxic, misfolded proteins, such as TDP-43, are implicated in diseases like amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
- Model organisms, like yeast, are crucial for identifying compounds that counteract these toxic proteins.
Purpose of the Study:
- To conduct a phenotypic screen for small molecules capable of reversing TDP-43 toxicity in yeast.
- To identify novel therapeutic agents for neurodegenerative diseases by exploring compound libraries.
Main Methods:
- A phenotypic screen was employed using yeast as a model organism to identify compounds mitigating TDP-43 toxicity.
- Hit compounds, specifically 8-hydroxyquinolines (8-OHQs), were analyzed for their selectivity and mechanisms of action.
- Comparative growth and molecular analyses were performed to assess metal chelation and ionophore activities.
Main Results:
- 8-hydroxyquinolines (8-OHQs) were identified as a class of compounds that reverse TDP-43 toxicity in yeast.
- Different 8-OHQs demonstrated selectivity in rescuing toxicities caused by TDP-43, α-synuclein, and polyglutamine proteins.
- 8-OHQs exhibited distinct metal chelation and ionophore activities, suggesting diverse protective mechanisms.
Conclusions:
- The diverse bioactivity of 8-OHQs highlights their potential to elicit distinct protective mechanisms against various neurotoxic proteins by modulating metal homeostasis.
- Tailoring 8-OHQ activity presents a viable therapeutic strategy for specific neurodegenerative diseases, supported by encouraging clinical trial results for Alzheimer disease.
