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Small-molecule dissolution of stress granules by redox modulation benefits ALS models
Hiroyuki Uechi1,2, Sindhuja Sridharan3,4, Jik Nijssen1
1Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
Nature Chemical Biology
|May 14, 2025
Summary
Lipoamide, a small molecule, prevents harmful stress granule condensation linked to neurodegenerative diseases. This compound shows promise in animal models, improving neuronal health and motor function in ALS-related conditions.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Neurodegenerative diseases like ALS are linked to mutations in stress granule proteins.
- Abnormal stress granule formation is a hallmark of these diseases, presenting a therapeutic target.
Purpose of the Study:
- To identify small molecules that can modulate stress granule formation.
- To investigate the mechanism of action of lipoamide on stress granule proteins.
Main Methods:
- Thermal proteome profiling to identify protein targets of lipoamide.
- In vitro assays to study condensate formation and dissolution.
- In vivo studies in animal models of aging and ALS.
Main Results:
- Lipoamide specifically prevents cytoplasmic condensation of stress granule proteins.
- It stabilizes intrinsically disordered proteins like SRSF1 and SFPQ.
- Lipoamide ameliorates aging-associated protein aggregation and motor deficits in ALS models.
Conclusions:
- Lipoamide is a well-tolerated small molecule that modulates stress granule condensation.
- Its mechanism involves redox regulation of stress granule formation via the lipoamide dithiolane ring.
- Lipoamide offers a potential therapeutic strategy for neurodegenerative diseases associated with aberrant stress granules.
