Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice

Authors: Jeremy M. Sullivan, Anna M. Bagnell, Jonathan Alevy, Elvia Mena Avila, Ljubica Mihaljević, Pamela C. Saavedra-Rivera, Lingling Kong, Jennifer S. Huh, Brett A. McCray, William H. Aisenberg, Aamir R. Zuberi, Laurent Bogdanik, Cathleen M. Lutz, Zhaozhu Qiu, Katharina A. Quinlan, Peter C. Searson, Charlotte J. Sumner

Published: 2024-05-22

DOI: 10.1126/scitranslmed.adk1358

Source: Full article

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Abstract

Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether barrier breakdown is sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies to mitigate barrier hyperpermeability are also limited. Dominant missense mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms of hereditary motor neuron disease. To gain insights into the cellular basis of these disorders, we generated knock-in mouse models of TRPV4 channelopathy by introducing two disease-causing mutations (R269C and R232C) into the endogenous mouse