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

• Published in: Nature communications Vol. 11; no. 1; pp. 1 - 17
• Main Authors: Woolums, Brian M., McCray, Brett A., Sung, Hyun, Tabuchi, Masashi, Sullivan, Jeremy M., Ruppell, Kendra Takle, Yang, Yunpeng, Mamah, Catherine, Aisenberg, William H., Saavedra-Rivera, Pamela C., Larin, Bryan S., Lau, Alexander R., Robinson, Douglas N., Xiang, Yang, Wu, Mark N., Sumner, Charlotte J., Lloyd, Thomas E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 29.05.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Antagonists; Axonal transport; Ca2+/calmodulin-dependent protein kinase II; Calcium (intracellular); Calcium (mitochondrial); Calcium ions; Calcium signalling; Calcium-binding protein; Calmodulin; Channel gating; Degeneration; Disorders; Fruit flies; Guanosine triphosphatases; Intracellular; Ion channels; Kinases; Mitochondria; Molecular modelling; Mutation; Neurodegeneration; Neurodegenerative diseases; Neuropathy; Neurotoxicity; Transient receptor potential proteins
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16411-5

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 (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.