Dysfunctional Chondroitin 4-O-Sulfotransferase-1 Impairs Cellular Redox State and Promotes Tau Aggregation

Chondroitin sulfate (CS) chains on the cell surface are sulfated in various patterns, and this structure is the basis of CS function. We aimed to investigate the role of chondroitin 4-<i>O</i>-sulfotransferase-1 (C4ST-1), the enzyme responsible for the 4-sulfation of CS, in redox homeostasis and protein aggregation in mouse neuroblastoma Neuro2a and neural progenitor C17.2 cells. Results showed that C4ST-1 deficiency significantly reduced 4-sulfated CS, which led to markedly decreased intracellular glutathione levels and increased reactive oxygen species production. Mechanistically, C4ST-1 loss reduced the CS modification of neurocan, decreased the stability of the cystine transporter xCT, and decreased intracellular glutathione levels. This redox imbalance promoted protein aggregation and caused lysosomal membrane damage, indicating a failure of protein quality control. Although C4ST-1 deficiency alone did not cause tau protein aggregation, it significantly accelerated the aggregation of a familial tauopathy mutant following the introduction of seeds. These findings suggest that C4ST-1-mediated CS sulfation regulates the intracellular redox state and tau pathology. Thus, C4ST-1 may serve as a therapeutic target for neurodegenerative diseases.