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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.
Plos Currents
|December 15, 2015
Summary
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.
