Emerging role of Nrf2 in Parkinson's disease therapy: a critical reassessment

Abstract

Parkinson's disease (PD) is the neurodegenerative disorder characterized by the progressive degeneration of nigrostriatal dopaminergic neurons, leading to the range of motor and non-motor symptoms. There is mounting evidence suggesting that oxidative stress, neuroinflammation and mitochondrial dysfunction play pivotal roles in the pathogenesis of PD. Current therapies only alleviate perturbed motor symptoms. Therefore, it is essential to find out new therapies that allow us to improve not only motor symptoms, but non-motor symptoms like cognitive impairment and modulate disease progression. Nuclear factor erythroid 2-related factor 2 (Nrf2) is transcription factor that regulates the expression of numerous anti-oxidants and cytoprotective genes can counteract oxidative stress, neuroinflammation and mitochondrial dysfunction, thereby potentially ameliorating PD-associated pathology. The current review discusses about the Nrf2 structure and function with special emphasis on various molecular signalling pathways involved in positive and negative modulation of Nrf2, namely Glycogen synthase kinase-3β, Phosphoinositide-3-kinase, AMP-activated protein kinase, Mitogen activated protein kinase, nuclear factor-κB and P62. Furthermore, this review highlights the various Nrf2 activators as promising therapeutic agents for slowing down the progression of PD.

Keywords: Mitochondrial dysfunction; Neuroinflammation; Nrf2; Oxidative stress; Parkinson’s disease.