The Role of P62/Nrf2/Keap1 Signaling Pathway in Lead-Induced Neurological Dysfunction

Area of Science:

• Neuroscience
• Toxicology
• Cell Biology

Background:

• Lead (Pb) exposure is a known risk factor for neurodegenerative diseases.
• The exact mechanisms of Pb-induced neurological damage are not fully understood.
• Oxidative stress and the autophagy pathway are implicated in neurodegeneration.

Purpose of the Study:

• To investigate the role of the P62/Keap1/Nrf2 pathway in Pb-induced neurotoxicity.
• To explore the interplay between oxidative stress, autophagy, and neurodegeneration in Pb exposure.
• To evaluate potential therapeutic interventions targeting this pathway.

Main Methods:

• In vivo and in vitro experimental models were utilized.
• Analysis of reactive oxygen species (ROS) production and protein expression (Keap1, Nrf2, HO-1, GPx).
• Investigation of P62 interactions within the Nrf2/Keap1 axis and Tau protein accumulation.

Main Results:

• Pb exposure increased ROS, upregulated Keap1, decreased Nrf2, and reduced antioxidant proteins (HO-1, GPx), causing oxidative damage.
• P62 interfered with autophagy via the Nrf2/Keap1 axis, leading to Tau accumulation and neurodegeneration.
• N-acetylcysteine, Artemisitene, and Rapamycin treatments ameliorated Pb-induced detrimental effects.

Conclusions:

• The P62/Nrf2/Keap1 pathway is a key mediator of Pb-induced neuronal dysfunction.
• This pathway represents a potential therapeutic target for neurodegenerative diseases linked to Pb exposure.
• Targeting oxidative stress and autophagy can mitigate lead's neurotoxic effects.