Charcot-Marie-Tooth disease (CMT) is a degenerative peripheral nerve disorder and the most commonly inherited neurologic disease. No effective treatments are currently available due in part to our incomplete understanding of disease mechanisms. Mutations in the calcium-permeable, non-selective ion channel transient receptor potential vanilloid 4 (TRPV4) result in a gain-of-channel function and cause CMT type 2C. This study seeks to determine whether alterations of channel activity stem from changes in TRPV4 post- translational modifications. Our preliminary data demonstrate that mutant TRPV4 shows deficits in ubiquitination that correlate with increased channel function. To further characterize TRPV4 ubiquitination and its role in regulating TRPV4 function, our first aim will identify specific lysine residues ubiquitinated within the TRPV4 N-terminus and characterize differences in ubiquitination between wildtype and mutant TRPV4. In our second aim, we will determine the effects of manipulating both wildtype and mutant TRPV4 ubiquitination on channel activity and localization. In order to measure the effect of TRPV4 ubiquitination on in vivo disease phenotypes, our third aim will explore whether manipulation of channel ubiquitination can ameliorate neuronal degeneration in a Drosophila model. These findings will significantly improve our understanding of the pathogenesis of CMT by defining a mechanism of mutant TRPV4 gain-of-channel function and determining whether TRPV4 can be therapeutically targeted. This work will not only provide important insights into the role of TRPV4 in neuronal health and disease, but will also inform future efforts to develop treatments for CMT and advance knowledge of the role of ubiquitination in degenerative neuropathy more broadly.
Charcot-Marie-Tooth (CMT) is the most common inherited neurological disorder causing progressive sensory and motor neuropathy, no treatment is currently available. Mutations of the calcium-permeable channel TRPV4 cause CMT 2C and result in a gain-of-channel function via unknown mechanisms. Studying TRPV4 ubiquitination in neurons will allow us to understand how this channel is regulated and elucidate mechanisms of disease that could support a novel therapeutic intervention.
