Parkinson's Disease Research Paper

Parkinson’s Disease and Effective Therapies

Carolyn Ardizzone

Molecular Neurobiology: Spring 2015

Introduction

Parkinson’s disease is a neurodegenerative disease affecting about 1 million people in the United States today (14). It is second in prevalence only to Alzheimer’s disease, with 1% of the population over 60 years old and 5% of the population over 85 years old with the disease (18). The average age of onset of the disease falls around 60 years old, but about 15% of people are diagnosed before age 50 (1). Although it is known to be a disease of the substantia nigra in the basal ganglia of the brain, the mechanisms producing the associated symptoms are yet to be discovered. Today, many of the therapies available to patients are developed

The SNpc is part of the larger basal ganglia that affects the motor cortex via the thalamus in the central nervous system. The thalamus intrinsically sends tonic inhibitory input to the motor cortex, suppressing motor function. Two pathways in the basal ganglia are capable of influencing this usual thalamic tonic inhibition – the indirect pathway and the direct pathway. The direct pathway flows from the cerebral cortex to the striatum to the internal segment of the globus pallidus, which synapses with the thalamus. The indirect pathway takes a similar route, but first detours from the striatum to the external segment of the globus pallidus, then the subthalamic nucleus, and then back to the internal segment of the globus pallidus. The net effect of the transient cortical activation of the direct pathway is an increase in motor movements, while transient cortical activation of the indirect pathway inhibits motor movements. The SNpc is relevant here because its neurons synapse with those of the striatum, an intermediate of both the direct and indirect pathways. However, the effect of its dopaminergic neurons on the cells of the striatum depends on the type of receptor present on the post-synaptic cells. The cells of the striatum with D1

At first it was hypothesized that dyskinesias might be caused by hypersensitive dopamine receptors in the striatum. If this were the case, however, dyskinesia would appear shortly after an initial dose of levodopa, but we instead see a gradual digression over multiple years. More recently there has been evidence that the knockout of D1 receptors in mice protects against levodopa-induced dyskinesia (LID) while knockout of D2 receptors produces no such protection. Furthermore, D1 receptors are not up-regulated after levodopa administration, no matter the length of treatment, in either humans or animal models with Parkinson’s, although there is not a solid consensus on these results. Regardless of the impact on the expression of these D1 receptors, there seems to be a link between the receptors’ sensitivity and the severity of LID in individuals. The patients that do not have dyskinesia seem to have a decrease in D1 receptor sensitivity following levodopa treatment while those who do have dyskinesia see an increase in receptor sensitivity. This sensitivity could be due to the location of D1 receptors on the cell membrane, as those with dyskinesia tend to have the same number of overall receptors, but have more receptors displaced from the synaptic membrane as compared to non-dyskinetic animals. There are many other theorized mechanisms for the dyskinesia that levodopa