Unknown

Dataset Information

0

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


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.

SUBMITTER: Woolums BM 

PROVIDER: S-EPMC7260201 | BioStudies | 2020-01-01

REPOSITORIES: biostudies

Similar Datasets

2018-01-01 | S-EPMC5970052 | BioStudies
1000-01-01 | S-EPMC3089570 | BioStudies
1000-01-01 | S-EPMC4884936 | BioStudies
2011-01-01 | S-EPMC3059145 | BioStudies
1000-01-01 | S-EPMC5809855 | BioStudies
2017-01-01 | S-EPMC5858867 | BioStudies
2017-01-01 | S-EPMC5460949 | BioStudies
2017-01-01 | S-EPMC5417564 | BioStudies
2017-01-01 | S-EPMC5792157 | BioStudies
2018-01-01 | S-EPMC5998047 | BioStudies