Our overall goal is to clarify what forms of subtle pathology underlie the functional losses that occur in diseases of myelinated nerve fibers. To pursue this goal we propose to examine in detail a recently discovered mouse mutant, 'shaking'that has marked CMS dysmyelination, yet, unlike other 'myelin mutants', does not progress to develop severe neurological abnormalities. Some shaking mice even improve with age, and lifespan is normal.
Our specific aims are to analyze the structure, behavior and electrophysiology of the 'shaking'mice in detail and in comparison other mutants that have superficially similar pathology but much greater neurological impairment in order to dissect out the specific features that disinguish the respective animals from one another and that may underlie the marked neurological disparities among them. These comparisons will be made at multiple time>points throughout the life span of the mice in order to assess progression. Analyses will make use of ultrastructural, freeze-fracture and immunofluorescence methods along with electrophysiologic measurements and behavioral tests to assess functional impairment. We also plan to undertake a positional cloning analysis to locate the gene defect in the new mutant. This study should clarify which specific components of myelinated nerve fibers lead to significant functional consequences when defective and which do not. The results may provide insight into the mechanisms underlying functional losses in human myelin diseases and suggest strategies for preventing or overcoming those losses. The factors underlying functional loss in human myelin diseases are unclear. Loss of myelin per se does not necessarily block conduction, and malfunctions clearly can occur even without overt demyelination. The proposed analysis of an animal model that has markedly abnormal myelin but little functional impairment will help to determine the functional importance of specific components of the axon/myelin sheath complex. These studies may clarify which spcific defects are responsible for functional impairment in human myelin diseases and may provide a basis for treatment or prevention.
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