Antioxidant and Anti-Inflammatory Defense in Huntington’s Disease: Role of NRF2 and Pgc-1α and Therapeutic Strategies

Abstract: Huntington’s disease (HD) is a detrimental neurodegenerative disease caused by the expansion of a CAG triplet in the HTT gene, ending in the production of abnormal Huntingtin (Htt) protein with toxic gain-of-function. The mutant protein (mHtt) is responsible in several ways for the establishment of an intricate pathogenetic scenario in affected cells, particularly in HD neurons. Among all the HD features, 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 antioxidants 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, aim of this re-view article is to describe the involvement of oxidative stress in HD by exploring the role of the NRF2 and PGC-1α, crucial actors in this play. Finally, antioxidant therapeutic strategies targeting such markers will be discussed.