p62-Keap1-NRF2-ARE Pathway: A Contentious Player for Selective Targeting of Autophagy, Oxidative Stress and Mitochondrial Dysfunction in Prion Diseases

Abstract

Prion diseases are a group of fatal and debilitating neurodegenerative diseases affecting humans and animal species. The conversion of a non-pathogenic normal cellular protein (PrPc) into an abnormal infectious, protease-resistant, pathogenic form prion protein scrapie (PrPSc), is considered the etiology of these diseases. PrPSc accumulates in the affected individual’s brain in the form of extracellular plaques. The molecular pathways leading to neuronal cell death in prion diseases are still unclear. The free radical damage, oxidative stress and mitochondrial dysfunction play a key role in the pathogenesis of the various neurodegenerative disorders including prion diseases. The brain is very sensitive to changes in the redox status. It has been demonstrated that PrPc behaves as an antioxidant, while the neurotoxic prion peptide PrPSc increases hydrogen peroxide toxicity in the neuronal cultures leading to mitochondrial dysfunction and cell death. The nuclear factor erythroid 2-related factor 2 (NRF2) is an oxidative responsive pathway and a guardian of lifespan, which protect the cells from free radical stress-mediated cell death. The reduced glutathione, a major small molecule antioxidant present in all mammalian cells, and produced by several downstream target genes of NRF2, counterbalances the mitochondrial reactive oxygen species (ROS) production. In recent years, it has emerged that the ubiquitin-binding protein, p62-mediated induction of autophagy, is crucial for NRF2 activation and elimination of mitochondrial dysfunction and oxidative stress. The current review article, focuses on the role of NRF2 pathway in prion diseases to mitigate the disease progression.

The ICP0 Protein of Herpes Simplex Virus 1 (HSV-1) Downregulates Major Autophagy Adaptor Proteins Sequestosome 1 and Optineurin during the Early Stages of HSV-1 Infection

“…However, NF-B is important for HSV-1 replication (71). In addition, p62 enables transcription of antioxidant proteins and detoxifying enzymes through the Keap-Nrf2 pathway (32,33,72). However, these antioxidant factors may negatively impact HSV-1 infection.…”

Protective effect of procyanidin B2 on hydrogen peroxide (H2O2)-induced oxidative damage in MCF-7 cells

“…Nrf2, as a considerable regulatory transcription factor upstream of antioxidant defense system, regulates the transcription expression of hundreds of antioxidant and detoxification related proteins [22]. Keap1 is a vital negative regulator of Nrf2 that regulates the relative expression levels of antioxidant proteins and phase II detoxification enzyme by interacting with antioxidant response elements [23]. As seen Fig.…”

The Potential Role of Nrf2 Signaling in Leishmania Infection Outcomes

“…Nrf2 is closely associated with the immune response to different types of antigens and the convergent signaling during pathogen recognition (Battino et al, 2018;Mohan and Gupta, 2018;Olagnier et al, 2018). By presenting an ambiguous response, that is, a response that favors either advanced infection or induces the microbicidal activity of defense cells, Nrf2 may be the crucial target of future pharmacological interventions (Deramaudt et al, 2013;Shah et al, 2018;Cuadrado et al, 2019). The molecular mechanisms of resistance conferred by Nrf2 in response to different levels of stress, such as that from intracellular infections, may vary according to the pathogen species and its virulence, as well as the host immune response, but there remain crucial processes that have not been very wellestablished and issues that need further study and analysis.…”