TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca2+

Brian M. Woolums, Brett A. McCray, Hyun Sung, Masashi Tabuchi, Jeremy M. Sullivan, Kendra Takle Ruppell, Yunpeng Yang, Catherine Mamah, William H. Aisenberg, Pamela C. Saavedra-Rivera, Bryan S. Larin, Alexander R. Lau, Douglas N. Robinson, Yang Xiang, Mark N. Wu, Charlotte J. Sumner () and Thomas E. Lloyd ()
Additional contact information
Brian M. Woolums: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine
Brett A. McCray: Department of Neurology, Johns Hopkins University School of Medicine
Hyun Sung: Department of Neurology, Johns Hopkins University School of Medicine
Masashi Tabuchi: Department of Neurology, Johns Hopkins University School of Medicine
Jeremy M. Sullivan: Department of Neurology, Johns Hopkins University School of Medicine
Kendra Takle Ruppell: Neurobiology Department, UMass Medical School
Yunpeng Yang: Department of Neurology, Johns Hopkins University School of Medicine
Catherine Mamah: Department of Neurology, Johns Hopkins University School of Medicine
William H. Aisenberg: Department of Neurology, Johns Hopkins University School of Medicine
Pamela C. Saavedra-Rivera: Department of Neurology, Johns Hopkins University School of Medicine
Bryan S. Larin: Department of Neurology, Johns Hopkins University School of Medicine
Alexander R. Lau: Department of Neurology, Johns Hopkins University School of Medicine
Douglas N. Robinson: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine
Yang Xiang: Neurobiology Department, UMass Medical School
Mark N. Wu: Department of Neurology, Johns Hopkins University School of Medicine
Charlotte J. Sumner: Department of Neurology, Johns Hopkins University School of Medicine
Thomas E. Lloyd: Department of Neurology, Johns Hopkins University School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract 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 (TRPV4R269C) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4R269C triggers increased intracellular Ca2+ through a Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca2+ and neurotoxicity in Drosophila and cultured primary mouse neurons. Importantly, TRPV4 activity impairs axonal mitochondrial transport, and TRPV4-mediated neurotoxicity is modulated by the Ca2+-binding mitochondrial GTPase Miro. Our data highlight an integral role for CaMKII in neuronal TRPV4-associated Ca2+ responses, the importance of tightly regulated Ca2+ dynamics for mitochondrial axonal transport, and the therapeutic promise of TRPV4 antagonists for patients with TRPV4-related neurodegenerative diseases.

Date: 2020
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DOI: 10.1038/s41467-020-16411-5

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