TRPV4‐mediated Ca²⁺ deregulation causes mitochondrial dysfunction via the AKT/α‐synuclein pathway in dopaminergic neurons

Abstract

Mutations in the gene encoding the transient receptor potential vanilloid member 4 (TRPV4), a Ca2+ permeable nonselective cation channel, cause TRPV4‐related disorders. TRPV4 is widely expressed in the brain; however, the pathogenesis underlying TRPV4‐mediated Ca2+ deregulation in neurodevelopment remains unresolved and an effective therapeutic strategy remains to be established. These issues were addressed by isolating mutant dental pulp stem cells from a tooth donated by a child diagnosed with metatropic dysplasia with neurodevelopmental comorbidities caused by a gain‐of‐function TRPV4 mutation, c.1855C > T (p.L619F). The mutation was repaired using CRISPR/Cas9 to generate corrected isogenic stem cells. These stem cells were differentiated into dopaminergic neurons and the pharmacological effects of folic acid were examined. In mutant neurons, constitutively elevated cytosolic Ca2+ augmented AKT‐mediated α‐synuclein (α‐syn) induction, resulting in mitochondrial Ca2+ accumulation and dysfunction. The TRPV4 antagonist, AKT inhibitor, or α‐syn knockdown, normalizes the mitochondrial Ca2+ levels in mutant neurons, suggesting the importance of mutant TRPV4/Ca2+/AKT‐induced α‐syn in mitochondrial Ca2+ accumulation. Folic acid was effective in normalizing mitochondrial Ca2+ levels via the transcriptional repression of α‐syn and improving mitochondrial reactive oxygen species levels, adenosine triphosphate synthesis, and neurite outgrowth of mutant neurons. This study provides new insights into the neuropathological mechanisms underlying TRPV4‐related disorders and related therapeutic strategies.

Aquaporin-4 and Parkinson’s Disease

“…The use of TRPV4 antagonist, AKT inhibitor, or α-synuclein knockdown induced the normalization of mitochondrial calcium levels in mutant neurons. These data suggest the importance of further investigation of such mechanisms due to their probable modulation by AQP4 and their impact on the pathogenesis of PD and other neurological disorders [148]. However, an in vivo study in a mouse MPTP model of PD revealed that adeno-associated virus (AAV)-induced TRPV4 knockdown alleviated movement deficits and nigral neurodegeneration in PD mice, whereas the upregulation of TRPV4 via the injection of a constructed AAV-TRPV4, aggravated it [149].…”