Regulatory proteins and epigenetic mechanisms including DNA methylation and histone modifications tightly control gene expression. Numerous studies have demonstrated that DNA methylation is dynamically regulated in post-mitotic neurons and critically impacts functions such as memory and synaptic plasticity. Our earliest findings revealed aberrant localization of the methylation enzyme DNMT1 in the cytoplasm of neuronal cells as a result of its interaction with aggregated alpha-synuclein, which accumulates in Lewy Bodies and is a major 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 tissue and blood from PD cases (Epigenetics 2013 8(10): 1030) encouraged our exploration of methylation signatures as potential biomarkers for PD diagnosis and/or to monitor disease-modifying therapies.
We are currently expanding our research by profiling larger cohorts of PD patients and control subjects, including longitudinal blood samples from the Harvard Biomarkers Study and the Parkinson’s Progression Markers Initiative. These efforts, supported by generous grants from the Michael J Fox Foundation, have already identified multiple pathways affected by epigenetic alterations that may contribute to disease progression and pathology, and which may be associated with responses to dopamine replacement therapy.