A role for epigenetic mechanisms in Lewy body dementias

Abstract:

BACKGROUND: The Lewy body diseases, Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and Parkinson's disease dementia (PDD) are all neurodegenerative diseases classified by the accumulation of alpha-synuclein in neurons, forming Lewy bodies (LB). We hypothesise that these LBs cause epigenetic changes within neurons and surrounding cells and that these changes can be used to distinguish the different LB diseases from one another. METHOD: Bulk tissue from the cingulate gyrus and prefrontal cortex will be as analysed for DNA methylation levels using the Illumina Infinium Methylation EPIC array to generate quantitative methylation data for over 850,000 CpG sites across the genome (n=∼100/disease group). Linear regression and pathway analyses will be used to identify loci that are significantly different or specific to each disease. Following this we will validate loci and determine their cellular specificity using a subset of samples (15 DLB, 15 PDD, 15 PD only, 15 controls) using fluorescence activated cell sorting (FACS). In each sample we will isolate various different cellular populations, including neurons, microglia, oligodendrocytes and astrocytes before profiling these using the EPIC array. RESULT: Study groups have been sourced consisting of cases with PD, PDD and DLB based on LB deposition and clinical symptom staging. Control cases have been selected for matched age and levels of concomitant AD pathology. Cases for FACS (n=15/group) have been selected to allow where possible a high base RIN, pH and minimal post-mortem interval. CONCLUSION: We are collating a well powered study cohort to interrogate the epigenetic basis of neuropathological progression and clinical staging of LB disease, controlling for levels of concomitant AD pathology. Follow up FACS sorting and analysis will allow for the cell specific methylation changes occurring in each of the LB diseases.