Translational research: development of a biomarker for Parkinson’s disease based on DNA methylation
Regulatory proteins and epigenetic mechanisms including DNA methylation and histone modifications tightly control gene expression. Increasing evidence supports the idea that DNA methylation is dynamically regulated in postmitotic neurons with crucial functions in memory and synaptic plasticity. Our earliest findings showed mislocalization of DNMT1 in the cytoplasm of neuronal cells, as a result of its interaction with aggregated ?-synuclein, the protein accumulated in Lewy Bodies and the pathological hallmark of Parkinson’s disease (PD). This abnormal localization was associated with global and gene specific changes in DNA methylation. Our subsequent study identifying concordant methylation changes in brain and blood from PD cases (Epigenetics 2013 8(10): 1030) encouraged the exploration of methylation signatures as potential biomarkers for PD diagnosis and/or to monitor disease-modifying therapies.
Accurate diagnosis of neurodegenerative diseases is hindered by the inaccessibility of the brain. Currently, it relies on evaluation of clinical features, however, overlapping symptoms across disorders might confound diagnosis, thus delaying proper interventions. Moreover, as clinical manifestation is preceded by a prodromal stage when neuronal degeneration is ongoing despite absence of symptoms, most of disorders are diagnosed very late. The goal of my group is to develop a biomarker panel based on quantification of DNA methylation on selected genes that can discriminate PD patients from healthy subjects in a simple blood test. This highly innovative approach, which represents the core of our translational research, is currently ongoing with funding from the Michael J. Fox Foundation (MJFF). We already completed genome-wide methylation screening on a cohort of 92 blood samples from PD and healthy control individuals. Following a comprehensive bioinformatics analysis, nurtured by collaborations with scientists at UCSD and John Hopkins University, we defined the best discriminant loci and we are currently testing potential screening approaches including a novel targeted method for next generation sequencing and a variation of high-resolution melting PCR.
We have been recently awarded a 2-year grant from MJFF, and in collaboration with Dr. Travis Dunckley at Arizona State University and Dr. Clemens Scherzer, at the Harvard Biomarker Study we are moving on the next step on a much larger cohort. This is the first longitudinal study of blood methylation biomarkers in PD, which also comprises the first epigenetic profiling from de novo patients, yet naïve to anti-parkinsonian treatments. This ambitious project includes the analysis of about 800 samples and will enable us to identify methylation signals that discriminate PD patients from healthy controls at early disease stages; while deciphering epigenetic changes associated with disease progression and treatment. In addition, this detailed analysis of methylation supported by comprehensive clinical characterization, will represent a unique repository of potential candidate genes, which might seed a myriad of new projects to understand the contribution of epigenetics to PD.