Establishing mechanisms of levodopa-induced dyskinesias in Parkinson’s disease in post-mortem human brain tissue

2017-01-31T00:01:27Z (GMT) by Cheshire, Perdita Anne
Parkinson‘s disease (PD) is a progressive and disabling neurodegenerative disease, characterized by a loss of dopamine neurons in the midbrain. Treatment of the motor symptoms of PD relies on replacing lost dopamine with dopaminergic drugs, in particular the pro-drug levodopa (L-DOPA). Chronic L-DOPA treatment leads to unwanted side-effects in the form of abnormal, involuntary movements (dyskinesias), which represent a major barrier to effective symptomatic management of PD. Although pre-clinical animal models provide compelling evidence as to the underlying mechanisms of levodopa-induced dyskinesias (LID), this has repeatedly failed to translate into treatment options Animal model data implicates both pre-synaptic and post-synaptic mechanisms of LID; namely that serotonin neurons cause LID by aberrantly releasing dopamine, and that post-synaptic dopamine receptors become hypersensitised to dopamine resulting in dyskinetic movements. Correlative data from human studies is notably lacking, but is a critical step in improving research translation. The research presented in this thesis aimed to address this translational gap by compiling two cohorts of post-mortem human brain tissue from PD patients characterised on the basis of their clinical LID phenotype, which provided an unprecedented opportunity to explore the pathophysiology of LID in PD. Studies were designed to determine whether hypotheses generated from animal models could be validated in human tissue. The results of these studies do not support a central role for serotonin neurons in LID, nor was post-synaptic sensitisation of dopamine receptors supported as a mechanism of LID. Putative genetic risk factors for developing LID identified from cross-sectional living cohorts were also excluded in a pathologicallyconfirmed study. The failure to demonstrate pathological markers of LID identified from animal models in human tissue challenges the adequacy of current pre-clinical animal models of LID, demonstrates the value of autopsy studies, and may go some way to explain why effective treatment of LID has so far proved elusive. These findings have important implications for the development of anti-dyskinetic agents but also contribute to the understanding of PD as a whole.