The NRF2-Dependent Transcriptional Regulation of Antioxidant Defense Pathways: Relevance for Cell Type-Specific Vulnerability to Neurodegeneration and Therapeutic Intervention

Abstract

Oxidative stress has been implicated in the etiology and pathobiology of various neurodegenerative diseases. At baseline, the cells of the nervous system have the capability to regulate the genes for antioxidant defenses by engaging nuclear factor erythroid 2 (NFE2/NRF)-dependent transcriptional mechanisms, and a number of strategies have been proposed to activate these pathways to promote neuroprotection. Here, we briefly review the biology of the transcription factors of the NFE2/NRF family in the brain and provide evidence for the differential cellular localization of NFE2/NRF family members in the cells of the nervous system. We then discuss these findings in the context of the oxidative stress observed in two neurodegenerative diseases, Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), and present current strategies for activating NFE2/NRF-dependent transcription. Based on the expression of the NFE2/NRF family members in restricted populations of neurons and glia, we propose that, when designing strategies to engage these pathways for neuroprotection, the relative contributions of neuronal and non-neuronal cell types to the overall oxidative state of tissue should be considered, as well as the cell types which have the greatest intrinsic capacity for producing antioxidant enzymes.

Normal and Pathological NRF2 Signalling in the Central Nervous System

“…Concerning the brain, numerous studies have described NRF2 as a transcription factor mainly expressed in glial cells [ 109 , 110 , 111 , 112 ]. Considering the Brain RNAseq data from Barres’ Lab ( accessed on 20 June 2022), NFE2L2 expression level is indeed stronger in glial cells (microglia, astrocytes) compared to neuronal cells in both mouse and human.…”

Activation of the Nrf2 Pathway as a Therapeutic Strategy for ALS Treatment

“…For instance, the aberrant activation of microglia with subsequent ROS generation and neurotoxic factors secretion is a common hallmark of several neurodegenerative disorders, including ALS [ 5 , 71 ]. As aforementioned, within the brain, Nrf2 transcript is found at higher levels in astrocytes and microglia than neurons [ 72 ], so that the activation of the Nrf2-associated pathway could represent a potential therapeutic strategy to inhibit the microglia-dependent inflammatory response [ 31 , 71 ].…”

“…Alternatively, PPI inhibitors could bind with high affinity with Keap1 partners inhibiting their functions. In both cases, subsequent unknown biological effects could arise [ 72 ]. A second very relevant issue is that Keap1 binds Nrf2 through its C-terminal Kelch domain, and dozens of human proteins with Kelch domain structurally very similar to the one in Keap1 exist [ 86 ].…”

“…In fact, a previous study showed that the activation of the Nrf2 antioxidant response was not sufficient to counteract oxidative stress in affected MNs [ 47 ]. As a possible explanation, using the cell-type-specific expression profiles of Nrf2 it was shown that Nrf2 expression is enriched in astrocytes, compared to neurons [ 72 ], suggesting that the dysregulation of the Nrf2 pathway could affect the protective functions mediated by astrocytes. Interestingly, the chemical activation of Nrf2 in astrocytes was sufficient to provide antioxidant protection to MNs [ 63 ].…”

“…The drug development of Nrf2 activators against ALS is also limited by the need for a defined molecule to pass the blood–brain barrier, and not to show off-target toxicity or adverse effects due to its multifactorial mode of action. In this context, the validation of the interactions between chemical probes and their intended targets in vivo, as well as the correlation with drug efficacy and drug toxicity, appears as a critical step for the subsequent clinical translation [ 72 ].…”