Charcot-Marie-Tooth (CMT) disease is the most common inherited neurologic disease worldwide and causes peripheral nerve degeneration with resultant progressive sensory loss and muscle weakness. Despite identification of over 80 causative genes, CMT lacks treatments due to incomplete understanding of disease mechanisms and a lack of rational drug targets. Mutations in TRPV4 (transient receptor potential vanilloid), a calcium-permeable non-selective ion channel, cause CMT type 2C (CMT2C). TRPV4 is unique in that it represents the only membrane-expressed ion channel in CMT and thus a potential therapeutic target. TRPV4 is known to regulate cytoskeletal changes in epithelial cells, but a similar role in neurons has not been established. As neuronal cytoskeletal changes are critical for neuronal development and maintenance and are regulated by calcium signaling, defining the role of TRPV4 in modulating neuronal cytoskeleton has important implications for the pathogenesis of CMT2C and potentially in other neurodegenerative conditions. Our collective preliminary work in cells, primary neurons, and flies suggests that TRPV4 can promote neurite outgrowth, but that this function is disrupted by neuropathy-causing mutations. We have also used unbiased proteomics to identify TRPV4 interacting proteins, including syndapin-1 and RhoA, which have known roles in regulating neuronal outgrowth.
Specific Aim 1 will define how WT and mutant TRPV4 influence syndapin-1 and RhoA-dependent cytoskeletal remodeling pathways and examine reciprocal regulation of TRPV4 ion channel function and mutant toxicity.
Specific Aim 2 will address the role of wild type and mutant TRPV4 in regulating neuronal morphogenesis in primary sensory and motor neurons.
In Specific Aim 3, we will use a Drosophila model of TRPV4 neuropathy and our recently generated TRPV4 mutant knockin mice to interrogate the in vivo effects of neuropathy mutations. We will also examine whether genetic manipulation of RhoA and syndapin or pharmacologic manipulation of TRPV4 channel activity can alter neuronal phenotypes in flies. The experiments in this proposal will define the normal function of TRPV4 in neuronal cytoskeletal remodeling and morphogenesis, investigate specific pathogenetic mechanisms in TRPV4 neuropathy, and determine whether TRPV4 can be therapeutically targeted in vivo. Together, these studies will provide important insights into the role of TRPV4 in axonal health and disease and will inform future efforts to develop TRPV4-based therapeutic strategies for CMT2C and perhaps other forms of axonal neuropathy.

Public Health Relevance

Charcot-Marie-Tooth (CMT) disease causes progressive sensory and motor neuropathy and is the most common inherited neurologic disorder, but no treatments are currently available. Mutations in TRPV4, a calcium-permeable, plasma membrane-localized ion channel, cause CMT type 2C through an unknown mechanism. This project will employ a combinatorial approach using primary neurons, flies, and mice to define how TRPV4 regulates cytoskeletal changes responsible for neuron development and maintenance and determine how these functions are disrupted by disease-causing mutations.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Neurological Sciences Training Initial Review Group (NST)
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Nuckolls, Glen H
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Johns Hopkins University
Schools of Medicine
United States
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