Mechanistic insights on the role of Nrf-2 signalling in Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder affecting individuals worldwide. It is characterized by progressive motor dysfunction, cognitive decline, and psychiatric disturbances. The pathogenesis of HD involves oxidative stress, neuroinflammation, and mitochondrial dysfunction. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating cellular responses to redox imbalance and inflammation, has emerged as a potential target for therapeutic intervention.

Through the use of a number of different search engines like Scopus, PubMed, Elsevier and Bentham, a literature review was carried out with the keywords ‘Huntington’s Disease, ‘Pathology of HD’ and ‘Nrf2 signalling pathway’. Using the keywords that were given above, this review was carried out in order to collect the most recent publications and gain an understanding of the breadth of the extensive research that has been conducted on the role of Nrf2 in HD pathogenesis.

Oxidative stress and neuroinflammation significantly contribute to HD progression. Activation of Nrf2 offers neuroprotection by enhancing anti-oxidant defense mechanisms. Furthermore, several signaling pathways, play crucial roles in HD pathophysiology. Pharmacological modulation of these pathways through selective inhibitors or agonists shows promise for the development of new therapeutic strategies.

The various downstream pathways such as extracellular signal-related kinase (ERK), phosphoinositide 3-Kinase (PI3-K), 5'-AMP-activated protein kinase (AMPK), Sirtuins, Mitogen-activated protein kinases (MAPK) plays a role in alleviating pathophysiology of HD. Diverse reports of these studies demonstrated PI3-K/AMPK/ERK/Sirtuins activators and MAPK inhibitors as encouraging targets in alleviating HD pathophysiology.