Hesperetin, Acting Through Inhibition of c-Jun Signaling, Mitigates Hypomyelinating Disease-Associated Stop-Loss Claudin-11-Induced Defective Morphogenesis in Oligodendroglial FBD-102b Cells.

Hypomyelinating leukodystrophies (HLDs) are a group of hereditary CNS disorders characterized by hypomyelination and, sometimes, repeated cycles of demyelination and remyelination. In HLDs, various genetic mutations in the responsible genes disrupt the morphogenesis of oligodendrocytes (oligodendroglial cells), which wrap neuronal axons with their differentiated myelin sheaths. A stop-loss mutation (c.622T-C or c.622T-G) in the gene encoding claudin family tetraspan plasma membrane protein claudin-11 (CLDN11) is associated with HLD22, which is characterized by incomplete differentiation and hypomyelination or delayed myelination in the brain. Herein, we describe for the first time that a CLDN11 mutant protein with an additional amino acid sequence due to the stop-loss mutation, but not the wild-type protein, leads to decreased expression of oligodendroglial differentiation marker proteins in the FBD-102b oligodendroglial progenitor cell line, the model undergoing its differentiation, at both the molecular and morphological levels. Consistently, mutant