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07:08
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Kinase inhibitors modulate huntingtin cell localization and toxicity
Randy Singh Atwal1, Carly R Desmond, Nicholas Caron
1Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Nature Chemical Biology
|May 31, 2011
Summary
Huntingtin phosphorylation at Ser13 and Ser16 impacts its nuclear localization and toxicity in Huntington's disease models. Kinase inhibitors targeting these sites show therapeutic potential for this neurodegenerative disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by mutations in the huntingtin gene.
- The N-terminal region of huntingtin (N17) plays a critical role in modulating mutant huntingtin toxicity.
- Specific serine residues in the N17 region are implicated in huntingtin's function and disease pathology.
Purpose of the Study:
- To investigate the role of huntingtin phosphorylation at Ser13 and Ser16 in Huntington's disease.
- To determine how N17 phosphorylation affects huntingtin's subcellular localization and conformation.
- To identify small-molecule modulators of N17 phosphorylation for potential therapeutic intervention.
Main Methods:
- Utilized cell and mouse genetic models of Huntington's disease.
- Analyzed huntingtin phosphorylation status in N17 using biochemical assays.
- Employed high-content screening in live cells to identify kinase inhibitors.
- Assessed huntingtin subcellular localization in response to kinase inhibition.
Main Results:
- Stress-dependent phosphorylation of huntingtin at Ser13 and Ser16 influences N17 conformation and subcellular targeting.
- Mutant huntingtin exhibits hypophosphorylation at N17 in HD models.
- Casein kinase-2 inhibitors reduced N17 phosphorylation, while IKKβ inhibition increased it, altering huntingtin localization.
- Identified kinase inhibitors that modulate N17 phosphorylation and huntingtin localization.
Conclusions:
- Huntingtin phosphorylation at Ser13 and Ser16 is a key regulator of its nuclear localization and function.
- Modulating N17 phosphorylation via kinase inhibitors offers a potential therapeutic strategy for Huntington's disease.
- These findings provide a basis for developing small-molecule drugs targeting huntingtin phosphorylation in HD treatment.
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