Charcot Marie Tooth disease (CMT) is the most common inheritable peripheral neuropathy in the United States. Individuals with CMT experience a range of symptoms, ranging from mild loss of motor coordination and some muscle weakness to debilitating pain and muscle weakness, often leading to the need for therapeutic intervention. Surprisingly, CMT is relatively underfunded (65 active NIH grants identified in a keyword search) compared to other peripheral neuron diseases such as amyotrophic lateral sclerosis (ALS;434 active NIH grants identified). In this proposal we develop and characterize a novel CMT mouse model that carries a human dynein mutation found in a hereditary form of CMT. Dynein is an essential molecular motor that functions to transport cargos along nerve axons. Several other human dynein mutations have recently been shown to cause other neurological disorders, suggesting that the study of dynein will become highly important in the future. We propose to characterize a human dynein disease allele in knock-in mice to examine the mechanism of disease onset and progression.
The first aim of the proposal is to characterize CMT disease onset and progression in the mutant mouse line with a battery of behavioral assays that examine phenotypes common to human presentation of CMT. In the second aim, we will examine the biochemical and biophysical properties of dynein in the mutant mouse strain. In the third aim we analyze intracellular transport of relevant neuronal cargoes. By correlating the behavioral phenotypes with the molecular characterization of the mutant dynein and cellular transport assays, we hope to generate a more comprehensive understanding of the key role dynein plays in neurological disease, ultimately leading to better human therapeutics including potential drug intervention strategies.
Charcot Marie Tooth disease is the most common peripheral neuropathy affecting the US population and has an enormous overall burden on the health system in the country. This project will develop and characterize a novel dynein mutant mouse that carries the same mutation that causes a specific form of Charcot Marie Tooth disease in humans. The exploratory approach in this study will validate this mouse model and use the mouse to determine how a molecular defect in the dynein gene causes the onset and progression of Charcot Marie Tooth disease.