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Updated: May 10, 2025
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Antioxidant and Anti-Inflammatory Defenses in Huntington's Disease: Roles of NRF2 and PGC-1α, and Therapeutic
Francesco D'Egidio1, Elvira Qosja2, Fabrizio Ammannito1
1Department of Life, Health and Environmental Sciences, University of L'Aquila, 67100 L'Aquila, Italy.
Insights
Huntington's disease involves oxidative stress damaging neurons. Antioxidant pathways, regulated by NRF2 and PGC-1α, offer potential therapeutic targets for this neurodegenerative condition.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by CAG triplet expansion in the HTT gene, producing toxic mutant Huntingtin (mHtt).
- Oxidative stress, characterized by mitochondrial dysfunction, ROS production, and reduced antioxidants, significantly contributes to HD pathogenesis and neuronal cell death.
- Neuronal cells possess intrinsic antioxidant defense mechanisms involving key regulatory factors.
Purpose of the Study:
- To review the critical role of oxidative stress in Huntington's disease progression.
- To explore the involvement and function of nuclear factor erythroid 2-related factor 2 (NRF2) and peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α) in HD-related oxidative stress.
- To discuss potential antioxidant therapeutic strategies targeting NRF2 and PGC-1α in HD.
Main Methods:
- Literature review focusing on the molecular mechanisms of oxidative stress in Huntington's disease.
- Analysis of the roles of NRF2 and PGC-1α in cellular defense against oxidative damage in HD models.
- Synthesis of current research on therapeutic interventions targeting antioxidant pathways.
Main Results:
- Mutant Huntingtin (mHtt) exacerbates oxidative stress through mitochondrial dysfunction and impaired antioxidant defenses.
- NRF2 and PGC-1α are crucial regulators of the cellular antioxidant response, and their dysfunction is implicated in HD.
- Dysregulation of these pathways contributes to the neurotoxic environment characteristic of Huntington's disease.
Conclusions:
- Oxidative stress is a central mechanism in Huntington's disease pathogenesis, driven by mHtt toxicity.
- NRF2 and PGC-1α represent key molecular players in the cellular antioxidant defense against HD.
- Targeting NRF2 and PGC-1α-mediated antioxidant pathways holds promise for developing novel therapeutic strategies for Huntington's disease.
Abstract:
Huntington's disease (HD) is a detrimental neurodegenerative disease caused by the expansion of a CAG triplet in the HTT gene. This mutation leads to the production of mutant Huntingtin (Htt) protein with toxic gain-of-function. The mHtt is responsible in several ways for the establishment of an intricate pathogenetic scenario in affected cells, particularly in HD neurons. Among the features of HD, oxidative stress plays a relevant role in the progression of the disease at the cellular level. Mitochondrial dysfunction, bioenergetic deficits, Reactive Oxygen Species (ROS) production, neuroinflammation, and general reduction of antioxidant levels are all involved in the promotion of a toxic oxidative environment, eventually causing cell death. Nonetheless, neuronal cells exert antioxidant molecules to build up defense mechanisms. Key components of these defensive mechanisms are the nuclear factor erythroid 2-related factor 2 (NRF2) and peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α). Thus, this review aims to describe the involvement of oxidative stress in HD by exploring the roles of NRF2 and PGC-1α, crucial actors in this play. Finally, antioxidant therapeutic strategies targeting such markers are discussed.
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