Objective: To resolve the inconsistencies in the magnitude and type of mitochondrial dysfunction within peripheral blood mononuclear cells (PBMCs) from people with Parkinson’s disease (PD), rapid eye movement behavior disorder (RBD) and matched healthy controls (HCs).

Background: There is growing evidence that mitochondrial dysfunction and oxidative stress play important roles in PD.  Increased ROS, decreased ATP production and impaired mitochondrial respiration all occur in the PD brain and are thought to play a major role in dopaminergic cell loss seen the disease.  The endogenous antioxidant response pathway protects cells from oxidative stress by increasing transcription of cytoprotective genes through the binding of the transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) to antioxidant response elements in the promoters of antioxidant genes. NRF2 has also been shown to participate in regulating mitochondrial function, highlighting its place at the intersection of these early cellular changes.  In fact, there is growing evidence of a relationship between NRF2 activity and PD – a functional haplotype in the human NFE2L2 promotor that increases the transcriptional activity of the gene was found to be associated with decreased risk and delayed onset of PD.

Method: We acquired cryopreserved PBMCs from three different populations: (1) RBD patients (n=25) were 18 years or older with PSG-confirmed RBD without parkinsonism or dementia; (2) PD (n=30) patients were 40 years or older, Hoehn & Yahr stage 2 or less, dichotomized into groups with high and low UPDRS scores; and (3) Age- and sex- matched PBMC samples from healthy controls (n=25). NRF2 gene expression was quantified by qPCR.

Results: There was a 1.66-fold change in NRF2 expression in PD patients with high UPDRS3 scores (mean 25±5.03) compared to low UPDRS3 scores (mean 15±4.62). Further analyses and group comparisons are needed and mitochondrial bioenergetics need to be profiled using the SeahorseXF analyzer which can sensitively measure basal respiration, ATP-linked respiration, proton leak and reserve capacity in live cells or isolated mitochondria, allowing for the detection of subtle alterations in mitochondrial function.

Conclusion: NRF2 expression is increased in patients with greater clinical burden.  Further studies exploring the magnitude and variability across the synucleinopathy spectrum are warranted

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MDS Abstracts - https://www.mdsabstracts.org/abstract/measures-of-mitochondrial-function-in-serum-across-the-parkinsons-disease-spectrum/