Related Experiment Video
Updated: Mar 28, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Thiol-disulfide Oxidoreductases TRX1 and TMX3 Decrease Neuronal Atrophy in a Lentiviral Mouse Model of Huntington's
Jonathan Fox1, Zhen Lu1, Lorraine Barrows
1Neuroscience Graduate Program, Department of Veterinary Sciences, University of Wyoming, Laramie, Wyoming, USA.
Insights
Researchers identified thioredoxin 1 and thioredoxin-related transmembrane protein 3 as key proteins that reduce mutant huntingtin levels, offering a potential new therapeutic strategy for Huntington's disease (HD). This discovery highlights the role of protein-thiol homeostasis in HD pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin gene (HTT).
- This expansion leads to the production of a polyglutamine-expanded mutant huntingtin protein (mHTT), whose N-terminal fragments accumulate in the brain, driving disease progression.
- Evidence suggests aberrant thiol oxidation plays a role in HD pathogenesis, implicating protein-thiol homeostasis.
Purpose of the Study:
- To identify specific thiol-disulfide oxidoreductases that can decrease mHTT levels in cells.
- To evaluate the neuroprotective effects of identified oxidoreductases in a mouse model of Huntington's disease.
Main Methods:
- An in-vitro genetic screen of thiol-disulfide oxidoreductases was performed to identify candidates that reduce soluble mHTT levels.
- Secondary screens were conducted to confirm mHTT-decreasing properties.
- A lentiviral mouse model of HD was used to test the efficacy of identified proteins in vivo, specifically examining their effect on striatal neuronal atrophy.
Main Results:
- In-vitro screening identified thioredoxin 1 (TXN1) and thioredoxin-related transmembrane protein 3 (TMX3) as proteins capable of reducing soluble mHTT levels in cultured cells.
- Both TXN1 and TMX3 demonstrated a protective effect in a mouse model of HD, significantly decreasing mHTT-induced striatal neuronal atrophy.
Conclusions:
- Thioredoxin 1 and thioredoxin-related transmembrane protein 3 are identified as key regulators that decrease mHTT levels.
- These findings support the hypothesis that targeting specific thiol-disulfide oxidoreductases could be a viable therapeutic strategy for Huntington's disease.
- The study underscores the importance of dysregulated protein-thiol homeostasis in the pathogenesis of HD, opening new avenues for therapeutic intervention.
Abstract:
Huntington's disease (HD) is caused by a trinucleotide CAG repeat in the huntingtin gene (HTT) that results in expression of a polyglutamine-expanded mutant huntingtin protein (mHTT). N-terminal fragments of mHTT accumulate in brain neurons and glia as soluble monomeric and oligomeric species as well as insoluble protein aggregates and drive the disease process. Decreasing mHTT levels in brain provides protection and reversal of disease signs in HD mice making mHTT a prime target for disease modification. There is evidence for aberrant thiol oxidation within mHTT and other proteins in HD models. Based on this, we hypothesized that a specific thiol-disulfide oxidoreductase exists that decreases mHTT levels in cells and provides protection in HD mice. We undertook an in-vitro genetic screen of key thiol-disulfide oxidoreductases then completed secondary screens to identify those with mHTT decreasing properties. Our in-vitro experiments identified thioredoxin 1 and thioredoxin-related transmembrane protein 3 as proteins that decrease soluble mHTT levels in cultured cells. Using a lentiviral mouse model of HD we tested the effect of these proteins in striatum. Both proteins decreased mHTT-induced striatal neuronal atrophy. Findings provide evidence for a role of dysregulated protein-thiol homeostasis in the pathogenesis of HD.
