Investigators/Authors: Giulietta Riboldi, MD, NYU School of Medicine
Objective: We propose to assess DNA methylation profiles in whole blood (WB) and isolated monocytes from PD patients and controls in order to study the role of the immune system in Parkinson’s disease.
Background:PD is the second most common degenerative disorder worldwide. Despite the identification of many different pathways that may play a central role in this disease, its pathogenic mechanisms are not yet clear. Because of this lack of knowledge, available treatments are mainly symptomatic. Cell-autonomous mechanisms seem to play an important role in the degeneration of the dopaminergic cells, which is the hallmark of the disease. However, microglia activation and its scavenger role in the elimination of alpha-synuclein, the interaction between the T-cell compartment and the role of dopaminergic neurons as antigen presenting cells (APC), all suggest an important role of inflammation in PD.
Methods/Design: Our goal is to profile epigenomic modifications such as DNA methylation in peripheral monocytes. Our rationale is that environmental exposures (smoking, caffeine, alcohol, organophosphate) and biophysical features (such as urate and flavonoids levels, hormonal therapy, physical activities) affect the incidence of PD. Environmental exposure may affect the epigenetic profiles of target tissues and modulate the inflammatory response through their effect on specific cell types.
We will recruit a population of 50 well characterized PD patients and 50 controls (defined as age- matched subjects that do not carry a diagnosis of neurodegenerative disease or chronic autoimmune disorder) and assess their exposure to risk factors previously associated with PD. Collected data will be used to define PD phenotypes and will be correlated with genome wide DNA methylation from isolated CD14+ monocytes. In addition, we aim to perform an integrated genomic analysis to correlate methylation profiles, expression profiles and genotype in whole blood from a large cohort (PPMI study) of PD patients and controls. These analyses will identify impaired pathways and signatures of the disease. Additionally, deconvolution analysis of our data will be performed to detect the contribution of different subpopulations of cells of the immune system to be then confirmed in isolated CD14+ monocytes. Lastly, we will generate genome-wide DNA methylation profiles from CD14+ monocytes in a pilot cohort of PD and control subjects.
Relevance to Diagnosis/Treatment of Parkinson’s disease: The project will help elucidate the role of the immune system in PD. DNA methylation signatures in blood cells could represent an easily accessible biomarker for the diagnosis, phenotypical stratification, and assessment of novel therapies for PD.
November 2020 Project Update:
Because of the recent COVID-19 pandemic and the consequent suspension of research visits at our Institution, our enrollment goal and sample collection has been significantly affected. Despite implementing remote assessments as much as possible, we will need to prologue our enrollment period. Also, pilot analysis of the data collected so far have been delayed by the recent closure of the labs due to the pandemic, further delaying the project.
October 2021 Project Update:
During the past year we successfully enrolled a cohort of subjects with Parkinson’s disease (PD) (n = 50) and non-affected age-matched controls (n = 50). For each enrolled subject, demographic and clinical information were collected, including motor and non-motor features of PD using standardized rating scales and questionnaires, as well as a detailed characterization of exposure to environmental factors (i.e. exposure to rural vs urban environments, smoke, alcohol, caffeine, heavy metal, anti-inflammatory medications, and history of head trauma).
Blood samples from the enrolled subjects are now being processed to isolate peripheral blood mononuclear cell (PBMC) and CD14+ monocytes, the cells of the innate immune system. DNA and RNA will be used to correlate gene expression in these cells type and modifications of the DNA through the assessment of the specific type of change called methylation. A pilot cohort (n = 16 samples) of PD and control subjects was processed to detect methylation changes. Quality control analysis of these data are ongoing, while the rest of the samples are processed and sent for methylation analysis.
In parallel, we also started analyzing the data from the Parkinson's Progression Markers Initiative (PPMI) database, considering clinical features, gene expression data, and methylation data from whole blood (WB). Our preliminary work supported a clear deregulation of gene expression in the inflammatory cells in subjects with PD compared to controls, as we reported in two manuscripts (one under revision and one in preparation). Interestingly, by analyzing previously collected data from the CD14+ monocytes, we were able to identify a set of deregulated genes overlapping with the ones from whole blood (PPMI cohort), suitable for further investigations.
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