DNA methylation changes associated with Parkinson’s disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood

Abstract

Parkinson's Disease (PD) is a common neurodegenerative disorder currently diagnosed based on the presentation of characteristic movement symptoms. Unfortunately, patients exhibiting these symptoms have already undergone significant dopaminergic neuronal loss. Earlier diagnosis, aided by molecular biomarkers specific to PD, would improve overall patient care. Epigenetic mechanisms, which are modified by both environment and disease pathophysiology, are emerging as important components of neurodegeneration. Alterations to the PD methylome have been reported in epigenome-wide association studies. However, the extent to which methylation changes correlate with disease progression has not yet been reported; nor the degree to which methylation is affected by PD medication.We performed a longitudinal genome-wide methylation study surveying~850,000 CpG sites in whole blood from 189 well-characterized PD patients and 191 control individuals obtained at baseline and at a follow-up visit~2 y later. We identified distinct patterns of methylation in PD cases versus controls. Importantly, we identified genomic sites where methylation changes longitudinally as the disease progresses. Moreover, we identified methylation changes associated with PD pathology through the analysis of PD cases that were not exposed to anti-parkinsonian therapy. In addition, we identified methylation sites modulated by exposure to dopamine replacement drugs.These results indicate that DNA methylation is dynamic in PD and changes over time during disease progression. To the best of our knowledge, this is the first longitudinal epigenome-wide methylation analysis for Parkinson's disease and reveals changes associated with disease progression and in response to dopaminergic medications in the blood methylome.

The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure

“…To further explore the significance of identified human DNMT1-dependent genes, we evaluated the recent literature on potential blood biomarkers in Parkinson's disease (PD) patients. Encouragingly, we observed five differentially methylated genes in these studies within our conserved human regions [29,75]. They are COL9A2, SCNN1A, AMICA1, SLC16A3, and DLK1.…”

“…They are COL9A2, SCNN1A, AMICA1, SLC16A3, and DLK1. One of these genes, COL9A2, was also found to be differentially expressed in our rotenone treated cells [29] (described below). Given that candidate PD biomarkers and our DNMT1-dependent genes were selected by differing criteria, we consider five overlapping genomic regions to be promising toward our hypothesis.…”

Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective

“…Clinical features of PD such as the delayed age of disease onset, low concordance rate (11%) between monozygotic twins 2, 3 , symptomatic fluctuations over disease course, including a unilateral to bilateral symptom presentation in most individuals (85%) 4,5 , and prominent sex differences in disease risk 6,7 , collectively suggest the contribution of the modifiable epigenome to disease origins and progression [8][9][10] . Although recent candidate-gene and array-based studies support that epigenetic abnormalities occur in PD tissues [10][11][12][13][14] , thus far, the epigenomes of PD patients remain largely unexplored and there has yet to be an epigenetic study of neurons from the PD brain.…”

“…The conversion of DNA methylation to hydroxymethylation (and eventual demethylation) is catalyzed by ten-eleven translocation (TET) enzymes, which have also been shown to impact neurodevelopment and synaptic transmission 18,[23][24][25] . Despite their roles in healthy neuronal functions, there have been relatively few genome-wide studies of DNA methylation in the PD brain [11][12][13] . These have focused on bulk brain tissue with a heterogeneous mixture of neurons and glial cells, using platforms that examine primarily CpG sites within coding regions (exons) and CpG islands [11][12][13] .…”

“…Despite their roles in healthy neuronal functions, there have been relatively few genome-wide studies of DNA methylation in the PD brain [11][12][13] . These have focused on bulk brain tissue with a heterogeneous mixture of neurons and glial cells, using platforms that examine primarily CpG sites within coding regions (exons) and CpG islands [11][12][13] . However, it is now established that DNA modification profiles strongly diverge between neurons and glial cell types, and a large proportion of DNA methylation in neurons occurs at non-CpG (CpH) sites 18,26,27 .…”