Mitochondrial dysfunction and increased glycolysis in prodromal and early Parkinson's blood cells

Abstract

Background: Although primarily a neurodegenerative process, there is increasing awareness of peripheral disease mechanisms in Parkinson's disease. To investigate disease processes in accessible patient cells, we studied peripheral blood mononuclear cells in recently diagnosed PD patients and rapid eye movement‐sleep behavior disorder patients who have a greatly increased risk of developing PD. We hypothesized that peripheral blood mononuclear cells may recapitulate cellular pathology found in the PD brain and investigated these cells for mitochondrial dysfunction and oxidative stress. Methods: Peripheral blood mononuclear cells were isolated and studied from PD patients, rapid eye movement‐sleep behavior disorder patients and age‐ and sex‐matched control individuals from the well‐characterized Oxford Discovery cohort. All participants underwent thorough clinical assessment. Results: Initial characterization showed that PD patients had elevated levels of CD14 + monocytes and monocytes expressing C‐C motif chemokine receptor 2. Mitochondrial dysfunction and oxidative stress were increased in PD patient peripheral blood mononuclear cells, with elevated levels of mitochondrial reactive oxygen species specifically in patient monocytes. This was combined with reduced levels of the antioxidant superoxide dismutase in blood cells from PD patients and, importantly, also in rapid eye movement‐sleep behavior disorder patients. This mitochondrial dysfunction was associated with a concomitant increase in glycolysis in both PD and rapid eye movement‐sleep behavior disorder patient blood cells independent of glucose uptake or monocyte activation. Conclusions: This work demonstrates functional bioenergetic deficits in PD and rapid eye movement‐sleep behavior disorder patient blood cells during the early stages of human disease. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson’s disease

“…The reduced numbers and more active state of monocytes in Syn rats, which are among the main producers of resolvins, and their full recovery following RvD1 treatment, suggest a role for these peripheral cells in the pathogenesis of PD. Our data are in line with other studies reporting peripheral inflammation in PD, including changes in patients' blood immune cells [60][61][62] . Of note, the reduction of peripheral monocytes in Syn rats might explain the increased Iba1 + cell numbers in SNpc, striatum and hippocampus, given that both resident microglia and infiltrated monocyte-derived macrophages can express Iba1, in line with recent evidence of monocyte, T-or B-cell infiltration in α-syn based models [63][64][65][66] .…”

Discordant transcriptional signatures of mitochondrial genes in Parkinson’s disease human myeloid cells

“…Using FACS, we did not observe any differences in the proportions of monocyte subpopulations in a subset of PD (n = 11) and control (n = 11) samples (P-value > 0.05, unpaired t-test) ( Fig. S13A), contrary to previous reports (44,45). Secondly, we performed scRNA-seq of CD14 + monocytes by multiplexing 10 individuals (seven PD, three controls, Table S15) on the 10x Chromium system with an expected yield of 20,000 single-cells.…”

“…Although dysregulation of mitochondrial homeostasis in PD has been previously reported, these studies were mostly restricted to studying dopaminergic neurons, fibroblasts or blood from individuals with PD (45,(48)(49)(50)(51)(52)(53)(54). Some functional work of PD monocytes with limited sample size has been published before, reporting altered phagocytosis, metabolic alterations, and increased activation status upon different stimuli, (13,23,44,45,55,56) but none of these studies performed unbiased transcriptome-wide gene expression analysis in a large PD cohort. Our work provides a unique view of monocyte transcriptome alterations associated with PD pathophysiology.…”

What's wrong with mitochondria in Parkinson's disease?

“…In this issue, a collaborative group from the University of Oxford reports on the formidable and important task of studying mitochondrial function and glycolysis in peripheral blood mononuclear cells (PBMCs) from PD patients, rapid eye movement (REM) sleep behavior disorder (RBD) patients (at increased risk for development of PD), and age‐ and sex‐matched controls . It is important for the interpretation of their results to note that PBMCs are typically composed of about 70% to 90% lymphocytes and 10% to 30% monocytes.…”