Glutathione peroxidase activity is neuroprotective in models of Huntington's disease

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Huntington's disease is a fatal neurodegenerative disorder.
• It is caused by a CAG repeat expansion in the huntingtin (Htt) gene.
• This expansion leads to a polyglutamine tract in the Htt protein, causing toxicity.

Purpose of the Study:

• To identify genes that suppress the toxicity of mutant huntingtin protein.
• To investigate the potential of glutathione peroxidases (GPxs) as a therapeutic strategy for Huntington's disease.

Main Methods:

• Conducted a genome-wide overexpression suppressor screen in yeast.
• Utilized genetic and pharmacological approaches in yeast, mammalian cells, and Drosophila.
• Assessed Huntington's disease-relevant metrics and autophagy inhibition.

Main Results:

• Identified 317 open reading frames (ORFs) that ameliorate mutant Htt toxicity.
• Discovered that glutathione peroxidases (GPxs) are potent suppressors of Htt toxicity.
• Demonstrated that GPx activity robustly improves Huntington's disease metrics in various models.
• Found GPx activity to be more protective than other tested antioxidant approaches.
• Showed that GPx activity does not inhibit autophagy, unlike many other antioxidants.

Conclusions:

• Glutathione peroxidases represent a promising therapeutic target for Huntington's disease.
• GPx mimetics are well-tolerated in humans, suggesting clinical applicability.
• This approach offers a novel strategy for managing Huntington's disease by enhancing antioxidant defenses without compromising essential cellular processes like autophagy.