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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.
Nature communications, 05/2020, Letnik: 11, Številka: 1Journal Article
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.
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in: SICRIS
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