The epigenome as a therapeutic target for Parkinson's disease

Parkinson’s disease (PD) is a common, progressive neurodegenerative disease characterised by degeneration of nigrostriatal dopaminergic neurons, aggregation of α-synuclein and motor symptoms. Current dopamine-replacement strategies provide symptomatic relief, however their effectiveness wear off over time and their prolonged use leads to disabling side-effects in PD patients. There is therefore a critical need to develop new drugs and drug targets to protect dopaminergic neurons and their axons from degeneration in PD. Over recent years, there has been robust evidence generated showing that epigenetic dysregulation occurs in PD patients, and that epigenetic modulation is a promising therapeutic approach for PD. This article first discusses the present evidence implicating global, and dopaminergic neuron-specific, alterations in the methylome in PD, and the therapeutic potential of pharmacologically targeting the methylome. It then focuses on another mechanism of epigenetic regulation, histone acetylation, and describes how the histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes that mediate this process are attractive therapeutic targets for PD. It discusses the use of activators and/or inhibitors of HDACs and HATs in models of PD, and how these approaches for the selective modulation of histone acetylation elicit neuroprotective effects. Finally, it outlines the potential of employing small molecule epigenetic modulators as neuroprotective therapies for PD, and the future research that will be required to determine and realise this therapeutic potential.

Exploring the cardiovascular disease continuum: blood pressure and target organ damage

Introduction The objectives of this thesis are to: (1) examine how ambulatory blood pressure monitoring (ABPM) refines office blood pressure (BP) measurement; (2) determine if absolute ambulatory BP or dipping status is better associated with target organ damage (TOD); (3) explore the association of isolated nocturnal hypertension (INH) with TOD; and (4) investigate the association of night-time BP with ultrasound markers of cardiovascular damage. Methods Data from the Mitchelstown Cohort Study was analysed to deliver objectives 1 and 2. Objective 3 was addressed by a systematic review and analysis of data from the Mitchelstown Study. A sample of participants from the Mitchelstown Study underwent an echocardiogram for speckle tracking analysis and carotid ultrasound to achieve objective 4. Results ABPM reclassifies hypertension status in approximately a quarter of individuals, with white coat and masked hypertension prevalence rates of 11% and 13% respectively. Night-time systolic BP is better associated with TOD than daytime systolic BP and dipping level. In multi-variable models the odds ratio (OR) for LVH was 1.4 (95% CI 1.1 -1.8) and for albumin:creatinine ratio ≥ 1.1 mg/mmol was 1.5 (95% CI 1.2 – 1.8) for each 10 mmHg rise in night-time systolic BP. The evidence for the association of INH with TOD is inconclusive. Night-time systolic BP is significantly associated with global longitudinal strain (GLS) (beta coefficient 0.85 for every 10 mmHg rise, 95% CI 0.3 – 1.4) and carotid plaques (OR 1.9 for every 10 mmHg rise, 95% CI 1.1 – 3.2) in univariable analysis. The findings persist for GLS in sex and age adjusted models but not in multivariable models. Discussion Hypertension cannot be effectively managed without using ABPM. Night-time systolic BP is better associated with TOD than daytime systolic BP and dipping level, and therefore, may be a better therapeutic target in future studies.