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

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 Trpv4 gene. TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss. Genetic deletion of the mutant Trpv4 allele from endothelial cells (but not neurons, glia, or muscle) rescued these phenotypes. Symptomatic mutant mice exhibited focal disruptions of blood–spinal cord barrier (BSCB) integrity, associated with a gain of function of mutant TRPV4 channel activity in neural vascular endothelial cells (NVECs) and alterations of NVEC tight junction structure. Systemic administration of a TRPV4-specific antagonist abrogated channel-mediated BSCB impairments and provided a marked phenotypic rescue of symptomatic mutant mice. Together, our findings show that mutant TRPV4 channels can drive motor neuron degeneration in a non–cell autonomous manner by precipitating focal breakdown of the BSCB. Further, these data highlight the reversibility of TRPV4-mediated BSCB impairments and identify a potential therapeutic strategy for patients with TRPV4 mutations. TRPV4-mediated BSCB breakdown is a reversible driver of motor neuron degeneration in mice. Editor’s summary TRPV4 (transient receptor potential vanilloid 4) is a mechanosensitive cation channel important for vascular function. TRPV4 mutations have been identified in patients with motor neuropathies, but it is unknown how functional alternations in this channel drive neurodegeneration. Sullivan et al. show that mice with gain-of-function mutations in Trpv4 developed progressive neurological symptoms that were associated with blood–spinal cord barrier breakdown and focal loss of motor neurons. Removal of Trpv4 from endothelial cells (but not other cell types) or treatment with a small molecule antagonist reversed pathology. These findings reveal a cascade of events that potentially drives neurodegeneration in TRPV4 channelopathies. —Daniela Neuhofer