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Title: Investigating the neuroprotective effects of histone deacetylase inhibitors in Parkinson's disease
Author: Harrison, Ian
ISNI:       0000 0004 4692 2609
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Parkinson's disease (PD) is the most common movement disorder and the second most common neurodegenerative disease affecting around 4 million people worldwide. Movement symptoms in PD are primarily due to degeneration of dopaminergic nigrostriatal neurons. These symptoms can be partially controlled by dopamine replacement therapies, however long term use of these drugs lead to debilitating side-effects and more importantly do not protect degenerating dopaminergic neurons from death. Hence novel neuroprotective strategies are sought. Recent evidence implicates ╬▒Synuclein accumulation, the hallmark of degenerating neurons in PD, with perturbed epigenetic acetylation of histone proteins around which DNA is coiled. A misbalance between the activities of the two enzyme classes responsible for control of histone acetylation, histone acetyltransferases and histone deacetylases (HDACs), have been linked to cell death in animal models of neurodegeneration. It is therefore hypothesised that if this pathogenic imbalance can be rectified with the use of HDAC inhibitors (HDACIs) then neurodegeneration observed in PD can be avoided. Here, the first evidence of altered histone acetylation and perturbed HDAC isoform expression in degenerating regions of the human Parkinsonian brain are demonstrated. Cell culture studies using dopaminergic neuronal and microglial cell lines demonstrate that dependent on the HDAC class(s) or isoform(s) inhibited, HDACIs are capable of inducing neuroprotection and reduction of microglial activation in vitro. Study of two broad-spectrum HDACIs in vivo, in the lactacystin rat model of PD demonstrate that, also dependent on isoform inhibition, HDACIs cause dose-dependent histone acetylation and upregulated expression of neurotrophic and neuroprotective factors, resulting in dopaminergic nigrostriatal neuroprotection and reduction of morphological changes and motor behavioural deficits detected through magnetic resonance imaging and behavioural testing respectively. Taken together the data herein provide compelling evidence to support the concept that dependent on isoform specificity, HDACIs represent a novel class of neuroprotective therapeutics for the treatment of PD.
Supervisor: Dexter, David Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available