Objective: To demonstrate the activation of Nuclear factor erythroid-2-related factor 2 (Nrf2) pathway in PD patients.

Background: Experimental data indicated the critical involvement of Nrf2 pathway in pathogenic mechanisms of PD, as well as its potential role as a target for disease-modifying treatments [1,2]. Surprisingly, such preclinical evidence has not been translated yet on a clinical ground.

Method: 32 PD patients and 32 sex/age-matched healthy controls were enrolled, receiving standardized clinical assessment. Nrf2 pathway was evaluated in blood leukocytes, by assessing Nrf2 transcript and protein levels, its downstream effectors (phase II and Glutathione metabolism enzymes) and upstream activators (redox state and mitochondrial function). Moreover, aimed at linking the pathway’s activity to intrinsic features of PD, we measured peripheral levels of α-synuclein (α-syn) oligomers and correlated biochemical data with clinical parameters. Mean and regression analysis were performed.

Results: In blood leukocytes of PD patients, Nrf2 was highly transcribed and expressed, as well as the target genes, NAD(P)H-Quinone-dehydrogenase-1 (Nqo1), Glutamate-Cysteine Ligase (GCL) and Glutathione Reductase (GR). The mitochondrial Complex I activity was decreased whereas the glutathione oxidized/reduced ratio was increased, both suggesting a significant alteration of the main activators of the Nrf2 pathway. Levels of α-syn oligomers were significantly increased. Of interest, Nrf2 and α-syn oligomers were associated to disease duration, directly and inversely respectively, indicating a dynamic occurrence of molecular events.

Conclusion: This study provides in vivo the unprecedented evidence that Nrf2 pathway is activated at systemic level in PD patients and is linked with synucleinopathy and clinical events. Therefore, our findings highlight the potential therapeutic implications of Nrf2 pathway in PD and also suggest that blood leukocytes reflect remote pathogenic mechanisms of the diseases, thus representing a potential source of biomarkers.

References: [1] M. Todorovic, S.A. Wood, G.D. Mellick, Nrf2: a modulator of Parkinson’s disease?, J. Neural Transm. 123 (2016) 611–619. doi:10.1007/s00702-016-1563-0. [2] H. Kumar, S. Koppula, I.-S. Kim, S.V. More, B.-W. Kim, D.-K. Choi, Nuclear factor erythroid 2-related factor 2 signaling in Parkinson disease: a promising multi therapeutic target against oxidative stress, neuroinflammation and cell death., CNS Neurol. Disord. Drug Targets. 11 (2012)

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nrf2-pathway-in-patients-with-parkinsons-disease/