Department of Neurobiology; Graduate School of Biomedical Sciences, Neuroscience Program; Yang Xiang Lab
Nervous System Diseases | Neuroscience and Neurobiology
The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4(R269C)) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4(R269C) triggers increased intracellular Ca(2+) through a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca(2+) and neurotoxicity in Drosophila and cultured primary mouse neurons. Importantly, TRPV4 activity impairs axonal mitochondrial transport, and TRPV4-mediated neurotoxicity is modulated by the Ca(2+)-binding mitochondrial GTPase Miro. Our data highlight an integral role for CaMKII in neuronal TRPV4-associated Ca(2+) responses, the importance of tightly regulated Ca(2+) dynamics for mitochondrial axonal transport, and the therapeutic promise of TRPV4 antagonists for patients with TRPV4-related neurodegenerative diseases.
Cellular neuroscience, Genetics of the nervous system, Ion channels in the nervous system, Peripheral neuropathies, Somatic system
Rights and Permissions
Copyright © The Author(s) 2020. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
DOI of Published Version
Woolums BM, McCray BA, Sung H, Tabuchi M, Sullivan JM, Ruppell KT, Yang Y, Mamah C, Aisenberg WH, Saavedra-Rivera PC, Larin BS, Lau AR, Robinson DN, Xiang Y, Wu MN, Sumner CJ, Lloyd TE. TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2. Nat Commun. 2020 May 29;11(1):2679. doi: 10.1038/s41467-020-16411-5. PMID: 32471994; PMCID: PMC7260201. Link to article on publisher's site
Woolums BM, Takle K, Xiang Y. (2020). TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca(2). University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1038/s41467-020-16411-5. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1695
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.