Session Information
Date: Tuesday, September 24, 2019
Session Title: Parkinsonisms and Parkinson-Plus
Session Time: 1:45pm-3:15pm
Location: Agora 3 West, Level 3
Objective: To investigate the use of PBMCs as a biomarker of mitochondrial dysfunction in Parkinson disease (PD) patients carrying pathogenic parkin or LRRK2 mutations.
Background: Mitochondrial dysfunction is thought to play a key role in the pathogenesis of PD. Both LRRK2 and biallelic parkin mutations can lead to genetic forms of PD. Both genes have also been implicated in maintaining mitochondrial function [1,2]. As such we investigated systemic mitochondrial dysfunction in these patients, with a view to developing blood based biomarkers of mitochondrial dysfunction in PD.
Method: Fresh PBMCs were isolated using Ficoll gradient separation from PD patients with pathogenic homozygous or compound heterozygous mutations in parkin or the G2019S mutation in LRRK2, as well as healthy controls (HC). PBMC mitochondrial function was analysed using Seahorse XF respirometry and flow cytometric assessment of mitochondrial membrane potential (Δψm) using TMRE staining.
Results: Nine parkin PD patients (average age 45.2yrs, 66% male), 5 LRRK2 PD patients (average age 60.8yrs, 80% female) and 24 healthy controls (average age 57.8yrs, 58% female) were sampled for the study. Both Parkin and LRRK2 patients had increased oxygen consumption related to proton leak (Parkin 2391 vs 0.88; p<0.01, LRRK2 2.35 vs 0.088; p=0.01). This is supported by both Parkin and LRRK2 patients having reduced lymphocyte resting Δψm (Parkin 134.2 vs 213.2; p=0.001, LRRK2 147.7 vs 213.2; p<0.05). Additionally Parkin patients were found to have reduced spare respiratory capacity, as reflected by the maximum/basal oxygen consumption ratio, (2.81 vs 3.10; p=0.02) compared to HC. Basal and ATP linked oxygen consumption were similar between all groups.
Conclusion: We have shown that PBMCs are a useful biomarker of mitochondrial dysfunction in a sub-groups of PD patients with pathogenic Parkin and LRRK2 mutations. These results are in keeping with the role of these two genes in maintaining proper mitochondrial function. The finding of normal basal oxygen consumption suggests that dysfunction is most pronounced when cells are under stress, during high ATP demand, such as the environment found in neurons. This ‘signature’ of mitochondrial dysfunction could be applied to idiopathic PD patients to define a mitochondrial subgroup, in which personalised, stratified therapeutics could be offered.
References: 1. Hattori N and Mizuno Y. Twenty years since the discovery of the parkin gene. J Neural Transm (Vienna) 2017; 124(9):1037-105. 2. Singh A, Zhi L, Zhang H. LRRK2 and mitochondria: Recent advances and current views. Brain Res 2019; 1702:96-104.
To cite this abstract in AMA style:
P. Campbell, J. Harvey, A. Costantini, H. Morris, A. Schapira. Peripheral Blood Mononuclear Cells (PBMCs) are Useful Biomarkers of Mitochondrial Dysfunction in Parkinson Disease Patients with Pathogenic Parkin and LRRK2 Mutations [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/peripheral-blood-mononuclear-cells-pbmcs-are-useful-biomarkers-of-mitochondrial-dysfunction-in-parkinson-disease-patients-with-pathogenic-parkin-and-lrrk2-mutations/. Accessed December 9, 2024.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/peripheral-blood-mononuclear-cells-pbmcs-are-useful-biomarkers-of-mitochondrial-dysfunction-in-parkinson-disease-patients-with-pathogenic-parkin-and-lrrk2-mutations/