Essential tremor (ET) is among the most common neurological diseases, occurring in 4% of adults age 40 and older, and even more frequently in advanced age (i.e., 7-8% by age 70 and >20% by age 90+). Despite its high prevalence, the underlying pathogenesis of ET is poorly understood, and, as a consequence, current treatments are empiric and have poor efficacy. Human postmortem studies are currently the most robust avenue for advancing the study of the underlying pathophysiological mechanisms of ET, as genes have yet to be identified for ET, and no transgenic mice currently exist to provide an animal model. Our group has been conducting systematic postmortem studies, which have revealed identifiable structural changes in the brains of ET cases. We have demonstrated that neuropathologic findings in the vast majority of ET cases (>90%) localize to the cerebellum itself and, in particular, to the Purkinje cells (PC), which provide the entire neuronal output from cerebellar cortex. In ET brains, there is a 6- to 7-fold increase in damaged PC axons, identified as rounded swellings of the proximal portion of the PC axon (i.e., """"""""torpedoes""""""""). Strongly correlating with this PC axonal damage is an approximate 30-40% reduction in the number of PCs and an increase in the number of heterotopic (displaced) PCs. Our ongoing pathologic studies further indicates that the torpedo is likely only a marker of advanced PC axonal damage. Earlier changes are now becoming evident in ET brains, including a graded increase in small to intermediate-sized thickenings of the proximal PC axon (i.e., presumed precursor- torpedoes) and increases in PC recurrent axon collateral formation with increased sprouting along the intracortical segment of PC axons. These studies implicate PC degeneration as a core feature of the disease process in ET, associated with slowly progressive axonal damage and significant remodeling of intracortical cerebellar connectivity. While these postmortem studies have advanced our understanding of disease pathogenesis to a cellular level, it is time to now proceed to a molecular understanding. In this proposal, we will address whether molecular alterations can be identified in cerebellar PCs from ET patients vs. neurologically normal controls. We will perform gene expression analyses by microarray screening on RNA isolated from PCs of ET versus control autopsy brains. We will employ laser-capture microdissection to specifically target PCs, thereby facilitating a precise evaluation of cell-specific changes associated with ET. ET brains will be limited to those with an absence of other neurodegenerative pathologies at autopsy. Analysis of the resultant expression data will identify genes and/or molecular pathways that are differentially expressed and/or biologically grouped in ET versus control PCs. Changes in gene expression will be validated by quantitative real time PCR. This study will be the first to initiate a molecular expression approach in ET research, and will provide a basis for proposing molecular causal mechanisms for ET that will be the focus of future investigations.
Essential Tremor (ET) is the most common cause of tremor in humans, affecting large numbers of individuals and families worldwide, yet until very recently its underlying pathological basis was unclear. Pathologic studies are now beginning to identify prominent structural changes in a particular cerebellar neuron, the Purkinje cell, in brains of individuals with ET, but the molecular events that lead to these cellular alterations are totally unknown. The approach proposed in this study will be the first attempt to use gene expression profiling methods in human Purkinje cells from ET versus neurologically normal brains, and will thereby provide a basis for proposing causal mechanisms in ET and a rationale for developing improved therapies in this disorder.
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