Background: Chen explains, "GSK3b is like an on/off switch for the detoxification system Nrf2. Endoplasmic reticulum stress can be caused by consistent and long-term activation of nociceptors as well as, abnormal dopamine flux by genetic alterations or environmental insults like the abuse or use of certain drugs. Dopamine-generated ER stress can activate the GSK3b response through PP2A that leads to neuronal death. This is the type of neuronal death that has been implicated in the neural degeneration seen in Parkinson's disease. Indications of ER dysfunction include unfolded protein response and may also activate the NF-kappa B inflammatory pathway. Other studies have shown it may be important in acute brain injury and other chronic degenerative diseases including Alzheimer's. GSK3b activity has been shown to be regulated by ER stress, oxidative stress, heat shock and and hyperosmosis."
- GDNF and BDNF provide protection against GSK3b but may be down-regulated in some instances of environmental illness.
- Inhibition of PP2a result in the inhibition of GSK3b activation leading to apoptosis (programmed cell death).
- Ceramide-dependant activation of PP2a leads to the downregulation of Nrf2. (Hagan)
- (R)-alpha-lipoic acid (LA) has been shown to positively regulate the gene expression of Nrf2 which is the basis of Tory Hagan's research, in addition to PP2A activity, at the Linus Pauling Institute at Oregon State University. Nrf2 up-regulates heat shock protein HO-1.
- PP2a increases parallel increases in a-synuclein. (Peng)
Conclusions: Nrf2 is a modulator of the effects of gasoneurotransmitters through HO-1. Its impairment can not only result in susceptability to the effects of CO, NO and H2S but also the effects of catecholamines (ie. dopamine) that are activated by stress as part of the stress response. Long-term continuous activation of endoplasmic reticulum stress with impairments in Nrf2 can lead to environmentally induced conditions such as neurodegenerative conditions and brain injury as well as other inflammatory consequences including mitochondrial deficiency. Muscarinic receptors upregulate Nrf2 and Chaudhuri demonstrates the increase or decrease of binding of pesticides to the muscarinic receptor depends on the type of pesticide and greatly influences the toxicity of the pesticide. In his study, he showed paraquat's toxicity was greater. In addition, agricultural products may be contaminated with other agents or include "inert" ingredients that increase their toxicity by negatively influencing the expression of Nrf2 and/or its downstream targets. Other environmental influences may include nutrition (ie. obesity, malnutrition and high fat diets), mitochondrial disease, genetic mutations in the dopamine transporter (DAT) or DJ-1, or those in Nrf2, contaminants like dioxin and endotoxin that activate the AhR all enhance toxicity and risk for environmental disease.
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