Experimental investigations into the pathophysiology of Huntington's disease.
Date
1998
Authors
Hebb, Matthew Olding.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
Planning and initiation of movement is dependent upon efficient processing of cortical and subcortical information through the basal ganglia. Pathology of the basal ganglia or its associated nuclei results in impairment of motor control. Parkinson's and Huntington's diseases are prominent neurodegenerative conditions that have principle pathologies in the substantia nigra and striatum, respectively. The etiology of Huntington's disease has been traced to a trinucleotide expansion at the 5'-terminal of the IT15 gene. This expansion is translated into a polyglutamine region on the protein product of this gene, huntingtin. The connection between the genetic mutation and the pathology of Huntington's disease is unknown and even the role of the normal form of huntingtin in the brain remains speculative. The striatum is a principle region of degeneration in Huntington's disease, and the loss of efferent transmission from this nucleus is thought to be responsible for the motor impairments in this condition.
We describe the application of antisense technology to the study of basal ganglia function and, particularly, the effects of striatal dysfunction on motor behavior and alterations in the functional activation of other motor-associated, subcortical regions. Unilateral suppression of stimulant-induced immediate early gene expression in the striatum produced robust rotational behavior and changes in the activation of several brain regions. In particular, the globus pallidus was disinhibited and was found to produce marked suppression of the observed motor asymmetry in these animals. Another prominent region that was affected by these conditions was the superior colliculus. The intermediate layers of this structure had different responses to a reduction in striatal and/or pallidal activity. These findings are in accord with clinical reports of motor symptomatology of Huntington's disease. A systematic comparison of subcortical changes in metabolic activation was performed between animals with unilateral antisense-mediated striatal suppression, which we suggest provides a novel animal model of Huntington's disease, and subjects that had unilateral depletion of mesencephalic dopamine (Parkinson's disease model). These alterations and their clinical relevance are discussed.
In an alternate study, we provide a novel description of the regulation of the Hdh gene (rat homologue of IT15) in the hypothalamus. The expression of huntingtin mRNA and protein was found to be significantly elevated (∼7-fold) in the arcuate nucleus of lactating females when compared to naive female or male animals. This expression was localized to astrocytes that appeared to form intimate contacts with the neurons of this region. Also, in the same animals, cells of the subependymal region of the third ventricle, directly overlying the arcuate nucleus, were found to have a dramatic induction of huntingtin expression. These findings suggest that alterations in neuroendocrine structure and function that have been previously described by others, may involve recruitment and differentiation of glia to regulate the metabolic activity in the hypothalamus. Furthermore, the association of huntingtin with such processes provides novel clues into the role of this protein in the normal brain. Future investigations into this phenomena may ultimately reveal cellular systems through which the mutated huntingtin protein mediates its pathological effects.
Thesis (Ph.D.)--Dalhousie University (Canada), 1998.
We describe the application of antisense technology to the study of basal ganglia function and, particularly, the effects of striatal dysfunction on motor behavior and alterations in the functional activation of other motor-associated, subcortical regions. Unilateral suppression of stimulant-induced immediate early gene expression in the striatum produced robust rotational behavior and changes in the activation of several brain regions. In particular, the globus pallidus was disinhibited and was found to produce marked suppression of the observed motor asymmetry in these animals. Another prominent region that was affected by these conditions was the superior colliculus. The intermediate layers of this structure had different responses to a reduction in striatal and/or pallidal activity. These findings are in accord with clinical reports of motor symptomatology of Huntington's disease. A systematic comparison of subcortical changes in metabolic activation was performed between animals with unilateral antisense-mediated striatal suppression, which we suggest provides a novel animal model of Huntington's disease, and subjects that had unilateral depletion of mesencephalic dopamine (Parkinson's disease model). These alterations and their clinical relevance are discussed.
In an alternate study, we provide a novel description of the regulation of the Hdh gene (rat homologue of IT15) in the hypothalamus. The expression of huntingtin mRNA and protein was found to be significantly elevated (∼7-fold) in the arcuate nucleus of lactating females when compared to naive female or male animals. This expression was localized to astrocytes that appeared to form intimate contacts with the neurons of this region. Also, in the same animals, cells of the subependymal region of the third ventricle, directly overlying the arcuate nucleus, were found to have a dramatic induction of huntingtin expression. These findings suggest that alterations in neuroendocrine structure and function that have been previously described by others, may involve recruitment and differentiation of glia to regulate the metabolic activity in the hypothalamus. Furthermore, the association of huntingtin with such processes provides novel clues into the role of this protein in the normal brain. Future investigations into this phenomena may ultimately reveal cellular systems through which the mutated huntingtin protein mediates its pathological effects.
Thesis (Ph.D.)--Dalhousie University (Canada), 1998.
Keywords
Biology, Anatomy., Biology, Molecular., Biology, Neuroscience.