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Published on: May 14, 2017
Impaired Redox Signaling in Huntington's Disease: Therapeutic Implications
Bindu D Paul1, Solomon H Snyder1,2,3
1The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Insights
Huntington's disease (HD) involves mutant huntingtin protein aggregation, causing neurodegeneration through oxidative stress and mitochondrial dysfunction. Understanding redox imbalance is key to developing new HD therapies.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Huntington's disease (HD) is a fatal neurodegenerative disorder.
- It is caused by expanded polyglutamine repeats in the huntingtin protein, leading to toxic mutant huntingtin (mHtt) aggregation.
- HD pathogenesis involves transcriptional dysregulation, metabolic pathway disturbances, oxidative stress, and impaired mitochondrial function.
Purpose of the Study:
- To review the current understanding of aberrant redox homeostasis in Huntington's disease.
- To explore the mechanisms linking redox imbalance to neurodegeneration in HD.
- To discuss potential therapeutic interventions targeting redox pathways.
Main Methods:
- Literature review of studies on Huntington's disease.
- Analysis of research on oxidative stress, antioxidant defense, and mitochondrial function in HD.
- Synthesis of information on the role of redox imbalance in HD pathophysiology.
Main Results:
- Mutant huntingtin (mHtt) aggregation is a primary driver of toxicity in HD.
- Elevated oxidative stress and imbalanced redox signaling are hallmarks of HD.
- Compromised mitochondrial function contributes to impaired bioenergetics and increased free radical production in HD cells.
Conclusions:
- Aberrant redox homeostasis, characterized by oxidative stress and mitochondrial dysfunction, is central to Huntington's disease neurodegeneration.
- Further research into the precise mechanisms linking redox imbalance to neurodegeneration is needed.
- Targeting redox pathways presents a promising therapeutic strategy for HD.
Abstract:
Huntington's disease (HD) is a neurodegenerative disease triggered by expansion of polyglutamine repeats in the protein huntingtin. Mutant huntingtin (mHtt) aggregates and elicits toxicity by multiple mechanisms which range from dysregulated transcription to disturbances in several metabolic pathways in both the brain and peripheral tissues. Hallmarks of HD include elevated oxidative stress and imbalanced redox signaling. Disruption of antioxidant defense mechanisms, involving antioxidant molecules and enzymes involved in scavenging or reversing oxidative damage, have been linked to the pathophysiology of HD. In addition, mitochondrial function is compromised in HD leading to impaired bioenergetics and elevated production of free radicals in cells. However, the exact mechanisms linking redox imbalance to neurodegeneration are still elusive. This review will focus on the current understanding of aberrant redox homeostasis in HD and potential therapeutic interventions.
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