Abstract
Reactive oxygen species (ROS) are signalling molecules used to regulate cellular metabolism and homeostasis. However, excessive ROS production causes oxidative stress, one of the main mechanisms associated with the origin and progression of neurodegenerative disorders such as Parkinson’s disease. NRF2 (Nuclear Factor-Erythroid 2 Like 2) is a transcription factor that orchestrates the cellular response to oxidative stress. The regulation of NRF2 signalling has been shown to be a promising strategy to modulate the progression of the neurodegeneration associated to Parkinson’s disease. The NRF2 pathway has been shown to be affected in patients with this disease, and activation of NRF2 has neuroprotective effects in preclinical models, demonstrating the therapeutic potential of this pathway. In this review, we highlight recent advances regarding the regulation of NRF2, including the effect of Angiotensin II as an endogenous signalling molecule able to regulate ROS production and oxidative stress in dopaminergic neurons. The genes regulated and the downstream effects of activation, with special focus on Kruppel Like Factor 9 (KLF9) transcription factor, provide clues about the mechanisms involved in the neurodegenerative process as well as future therapeutic approaches.
Highlights
Published: 20 October 2021Aerobic organisms use oxygen for energy production and product detoxification, typically in organelles such as mitochondria and peroxisomes
The enzymes and proteins involved in cell protection against oxidative stress, as well as genes associated with familial forms of Parkinson’s disease (PD), are, in many cases, present in astrocytes or microglial cells, and not necessarily in neurons: GSH formation requires the interplay between different cells, neuromelanin accumulated inside dopaminergic neurons can be released and activate microglial cells, and strong evidence supports non-cell autonomous degeneration in PD [117,118], including the evidence of cell to cell propagation of synuclein and fibrillary tangles [119]
We found that Angiotensin II (AngII) and 6-OHDA induce an increase in the levels of Reactive oxygen species (ROS), and this increase was associated with an upregulation in NRF2-regulated genes Heme Oxygenase 1 (HMOX1) and NQO1 in dopaminergic neurons, both in culture and in vivo [28]
Summary
Aerobic organisms use oxygen for energy production and product detoxification, typically in organelles such as mitochondria and peroxisomes. Oxidative stress is the imbalance between ROS generation and its reduction and it is often the origin or hallmark of many diseases. Cells evolved different mechanisms such as transcriptional control of antioxidantrelated genes, targeted degradation of proteins, and controlled, targeted degradation of the source of ROS by different mechanisms. NFE2L2) is known as a master regulator of the antioxidant response [1], as it is known to regulate a great variety of genes with important functions in regulating the oxidative stress response and related pathways. We focus our attention on those mechanisms that increase the production of ROS in neurodegenerative diseases, especially PD, and on how the cells in the nervous system respond to oxidative stress.
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