| الوصف: |
Parkinson's disease (PD) is a common neurodegenerative disorder associated with the loss of dopamine neurons located in the substantia nigra pars compacta. Current pharmacological approaches for the treatment of PD are confounded by development of abnormal involuntary movements called dyskinesias, and offer limited long-term utility because they do not stop the disease progression. Accordingly, this thesis addressed two primary issues limiting the present treatments of Parkinson's disease: the molecular basis of dopamine receptor-related dyskinesias, and attenuation of dopamine neuron death. Administration of dopamine receptor agonists to rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathway produce changes in the denervated striatum that enable subsequent exposure to dopamine agonists to elicit potentiated circling behaviour, a phenomenon called "priming". Priming is used as a model to study the molecular basis of dyskinesias. Here, I demonstrate that dopamine D1-receptor priming is associated with a profound elevation of the nuclear transcription factor FosB in the denervated striatum. Moreover, intrastriatal delivery of an antisense oligonucleotide to fosB effectively blocked the induction of striatal FosB by dopamine agonist administration and attenuated the circling response elicited by injection of a selective dopamine D1-receptor agonist 3 days later. These findings suggest that dopamine receptor mediated FosB expression in the striatum plays a role in priming. In addition, the results from this study suggest that fosB may be involved the intracellular events which are responsible for the development of dyskinesias following chronic dopamine replacement therapy. The molecular processes which mediate the loss of nigral dopamine neurons in Parkinson's disease are not known. Recently, a novel family of mammalian proteins, called Inhibitor of Apoptosis (IAP) proteins, were cloned and shown to prevent cell death induced by a variety of cytotoxic factors. In two separate studies, I demonstrate that enhanced neuronal expression of two of these IAP proteins, neuronal apoptosis inhibitor protein (NAIP) and X-linked IAP (XIAP), prevents the death of nigral dopamine neurons following exposure to the dopaminergic neurotoxins. In rats, intrastriatal administration of recombinant adenoviruses containing NAIP (Ad.NAIP) was shown to prevent both the cellular and behavioural deficits produced by intrastriatal administration of 6-OHDA when compared to adenovirus control (Ad.lacZ) lesioned animals. Secondly, I describe a novel strain of mice engineered to overexpress XIAP in neurons by using a neuron-specific enolase promoter (NSE-xiap). Moreover, I demonstrate that NSE-xiap mice were profoundly resistant to the deleterious effects of the dopaminergic neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Since administration of MPTP can produce behavioural and neuropathological deficits reminiscent of PD in humans, results from this study suggest that IAP proteins may have utility for the treatment and prevention of cell death in idiopathic PD. Taken together, these studies suggest that neuroprotective strategies based on enhanced neuronal expression of IAP proteins may have novel therapeutic potential for treating neurodegeneration associated with Parkinson's disease. |
