Given this study:
Neurons depend on mitochondria for homeostasis and survival, and thus, mitochondrial dysfunction has been implicated in neurodegenerative diseases, including Parkinson's disease (PD). Increasing evidence indicates the mitochondrial uncoupler, 2,4-dinitrophenol (DNP), protects neurons against neurodegeneration and enhances neural plasticity. Here, the authors evaluated the protective effects of intraperitoneally (i.p.) administered low dose DNP in an acute mouse model of PD. Mice were administered DNP (1 or 5mg/kg) for 12 consecutive days, and then on day 13, MPTP (20mg/kg, i.p.) was administered four times (with 2h intervals between injections) to induce PD. It was found that MPTP-induced motor dysfunction was ameliorated in the DNP-treated mice versus vehicle-treated controls. Additionally, DNP effectively attenuated dopaminergic neuronal loss observed in MPTP treated mice. Moreover, in primary cultured neurons, DNP at 10μM, but not at 100μM, prevented MPP+-induced cell death and mitochondrial membrane potential (MMP) reduction. In addition, DNP was observed to cause the nuclear translocation of Nrf2 in primary neurons. Taken together, these findings of the present study suggest that DNP protects dopaminergic neurons against neurodegeneration and maintains MMP integrity in PD by activating adaptive stress responses.
"DNP was observed to cause the nuclear translocation of Nrf2 in primary neurons" Activation of nrf-2 protected the cells. Why was nrf-2 not providing protection before? Dysfunction of KEAP-1?
Doing an image search on nrf-2 here's a basic diagram: https://cdn.ncbi.nlm.nih.gov/p...
P62 may need to be added to that diagram
In mammals, the Keap1-Nrf2-ARE pathway (henceforth, "the Nrf2 pathway") and autophagy are major intracellular defence systems that combat oxidative damage and maintain homeostasis. p62/SQSTM1, a ubiquitin-binding autophagy receptor protein, links the Nrf2 pathway and autophagy. Phosphorylation of p62 dramatically enhances its affinity for Keap1, which induces Keap1 to release Nrf2, and the p62-Keap1 heterodimer recruits LC3 and mediates the permanent degradation of Keap1 in the selective autophagy pathway. Eventually, Nrf2 accumulates in the cytoplasm and then translocates into the nucleus to activate the transcription of downstream genes that encode antioxidant enzymes, which protect cells from oxidative damage. Since Nrf2 also upregulates the expression of the p62 gene, a p62-Keap1-Nrf2 positive feedback loop is created that further enhances the protective effect on cells. Studies have shown that the p62-activated noncanonical Nrf2 pathway is an important marker of neurodegenerative diseases. The p62-Keap1-Nrf2 positive feedback loop and the Nrf2 pathway are involved in eliminating the ROS and protein aggregates induced by AD. Therefore, maintaining the homeostasis of the p62-Keap1-Nrf2 positive feedback loop, which is a bridge between the Nrf2 pathway and autophagy, may be a potential target for the treatment of AD.
Activating p62 might help? Something like green tea extract?
"EGCG activates Keap1/P62/Nrf2 pathway"
https://pubmed.ncbi.nlm.nih.go...
Or maybe its too much autophagy, too low of nutrient?
Low cellular nutrient levels can also activate autophagy, which acts to restore metabolic homeostasis through the degradation of macromolecules to provide nutrients. (..) Dysregulation of autophagy was shown to result in prolonged Nrf2 activation in a p62-dependent manner. https://pmc.ncbi.nlm.nih.gov/a...
