Systemic Activation of Nrf2 Pathway in Parkinson's Disease

Abstract

Background Preclinical studies underlined the relevance of Nuclear factor erythroid 2‐related factor 2 (Nrf2) transcription factor pathway in the pathogenesis of Parkinson's disease (PD). Objective The objective of this study was to explore Nrf2 pathway in vivo in PD, looking for novel disease biomarkers and therapeutic targets. Methods The levels of Nrf2, the downstream effectors (NAD(P)H dehydrogenase [quinone] 1 (Nqo1) enzyme, glutathione metabolism enzymes Glutamate–cysteine ligase (GCL) and Glutathione Reductase (GR)), the upstream activators (redox state and mitochondrial dysfunction), and α‐synuclein oligomers were assessed in the blood leukocytes of PD patients comparatively to controls. Biochemical data were correlated to clinical parameters. Results In PD, Nrf2 was highly transcribed and expressed as well as its target effectors. The mitochondrial complex I activity was reduced and the oxidized form of glutathione prevailed, disclosing the presence of pathway's activators. Also, α‐synuclein oligomers levels were increased. Nrf2 transcript and oligomers levels correlated with PD duration. Conclusions Blood leukocytes mirror pathogenic mechanisms of PD, showing the systemic activation of the Nrf2 pathway and its link with synucleinopathy and clinical events. © 2019 International Parkinson and Movement Disorder Society

The Role of Oxidative Stress in Parkinson’s Disease

“…The expressions of NRF2 and NQO1 in DAergic neurons derived from iPSCs carrying a PARKIN mutation are also down-regulated [ 97 ]. Recently, a small clinical study demonstrates that levels of NRF2 in peripheral leukocytes are elevated in PD patients [ 183 ]. Larger studies with correlation between NRF2 pathway and clinical severity in PD are warranted to confirm the potential of NRF2 as a biomarker for PD.…”

Peripheral Blood NRF2 Expression as a Biomarker in Human Health and Disease

“…Furthermore, elevated levels of urate, a known NRF2 activator, is protective in a familial form of PD [51]. There was also shown to be a positive correlation between NRF2 transcript levels in PBMCs and disease duration [33] in non-genetically defined PD patients. These studies all suggest that NRF2 expression and function are likely beneficial in the context of PD.…”

COVID-19: dealing with a potential risk factor for chronic neurological disorders

“…PD is the second most common neurodegenerative disorder, characterized by progressive motor and non-motor disturbances, due to the loss of dopaminergic cells in the substantia nigra pars compacta (SNpc) and the accumulation of α-synuclein (α-syn)-positive Lewy bodies [7][8][9]. The relationship between viral infections and PD has its roots in the early twentieth century, when a number of post-encephalitic parkinsonism were observed following an influenza outbreak.…”

“…Further experimental evidence showed that Influenza-A virus disrupts mitochondrial activity and increase oxidative stress [ 12 , 13 ], whereas hepatitis C virus impairs dopaminergic transmission and affects the blood–brain barrier (BBB) integrity [ 10 ]. Therefore, viral infections may intervene in cellular pathways critical for PD pathogenesis, probably contributing to the initiation of the disease [ 8 , 9 , 14 – 17 ].…”