TRPV4-mediated Ca 2+ deregulation causes mitochondrial dysfunction via the AKT/α-synuclein pathway in dopaminergic neurons.
FASEB BioAdvances(2023)
摘要
Mutations in the gene encoding the transient receptor potential vanilloid member 4 (TRPV4), a Ca permeable nonselective cation channel, cause TRPV4-related disorders. TRPV4 is widely expressed in the brain; however, the pathogenesis underlying TRPV4-mediated Ca 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 Ca augmented AKT-mediated α-synuclein (α-syn) induction, resulting in mitochondrial Ca accumulation and dysfunction. The TRPV4 antagonist, AKT inhibitor, or α-syn knockdown, normalizes the mitochondrial Ca levels in mutant neurons, suggesting the importance of mutant TRPV4/Ca/AKT-induced α-syn in mitochondrial Ca accumulation. Folic acid was effective in normalizing mitochondrial Ca 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.
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关键词
calcium,dental pulp stem cells,mitochondria,transient receptor potential vanilloid member 4,α‐synuclein
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