Eve, David John; (1999) Investigation of gene expression in Parkinson's disease; Studies in human post mortem material and animal models. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The main lesion in Parkinson's disease is the loss of the dopaminergic nigrostriatal pathway, causing a multitude of 'downstream' changes in neuronal activity within the basal ganglia. We set out to investigate this by measuring mRNA expression for neurotransmitters or regulatory enzymes within the basal ganglia by quantitative autoradiographic in situ hybridisation. The striatal interneurons generally express the neurotransmitters GABA, or somatostatin and nitric oxide, or acetylcholine. They interact with both striatal afferents and afferents and therefore could exert an important integrative role over the activity of the basal ganglia. These neurotransmitters are also found in other areas of the basal ganglia potentially subject to PD-induced changes in activity but have been little studied mRNA expression for these neurotransmitters or their synthetic enzymes was therefore measured within the basal ganglia, including the striatum. Flash frozen post mortem material from human patients with Parkinson's disease or no neurological disorder, and unilaterally MPTP-lesioned vervets was available for study. Using cerebellar pH values as an indirect measure of agonal state, a correlation with mRNA preservation was observed which proved to be useful for creating analogous patient groups for study We detected decreased glutamate decarboxylase (GABA) mRNA in the external globus pallidus and increased nitric oxide synthase mRNA within the subthalamic nucleus as predicted from animal models. Increased nitric oxide and somatostatin were observed within the medial medullary lamina which could interact with the nigrostriatal pathway. Striatal intemeuronal neurotransmitter expression varied in a regional manner dependent on the neurotransmitter investigated. Decreased GABA was observed in the internal globus pallidus in opposition to the predicted increase, possibly due to the patients exhibiting 1-DOPA induced dyskinesias. This study shows that in situ hybridisation can provide important insights into neurotransmitter expression in post mortem material and hence the pathophysiology of Parkinson's disease.

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