NRF2 AT THE CROSSROADS OF PARKINSON'S DISEASE AND AGING: MECHANISTIC INSIGHTS AND TRANSLATIONAL PERSPECTIVES.

Abstract

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder characterized by dopaminergic neuronal loss, α-SYNUCLEIN aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) orchestrates cellular defense mechanisms by controlling genes involved in antioxidant responses, detoxification, and proteostasis. Impaired NRF2 signaling in PD amplifies oxidative damage, protein misfolding, and inflammatory cascades, whereas NRF2 activation confers broad neuroprotection. This review summarizes evidence from cellular, animal, and human studies delineating NRF2 regulatory roles in redox homeostasis, mitochondrial integrity, and microglial activation. In preclinical models, NRF2 deficiency accelerates neurodegeneration, while pharmacological activation with agents such as dimethyl fumarate, sulforaphane, and synthetic triterpenoids mitigates dopaminergic loss and neuroinflammation. Human studies reveal altered NRF2 pathway components in PD brain and peripheral tissues, and genetic variants in NFE2L2 influence disease susceptibility and progression. Aging, PD's strongest risk factor, reduces NRF2 responsiveness through epigenetic and post-translational changes, promoting oxidative vulnerability and inflammaging. Environmental exposures, including pesticides and pollutants, further modulate NRF2 activity, compounding risk via cumulative "exposome" effects. Understanding NRF2 regulation provides mechanistic insight into PD pathogenesis and positions NRF2 activation as a promising therapeutic strategy for disease modification and healthy brain aging.