Characterization of dermatan sulfate and chondroitin sulfate profiles during brain regeneration in Styela plicata

Neuroregeneration is the ability of nervous tissue to renew itself after injury. This process is highly limited in mammals. In contrast, marine chordates such as ascidians display a remarkable regenerative capacity, making them valuable models to understand neural regeneration. This study investigated dermatan sulfate (DS) and chondroitin sulfate (CS) profiles during brain regeneration in the ascidian Styela plicata. Neurodegeneration was induced by 3-acetylpyridine (3-AP), after which neural complex (NC) analyses were conducted using histology, RT-qPCR, liquid chromatography, behavioral testing, and phylogenetic methods at 1,5 and 10-day postinjection. One day after treatment, the cerebral ganglion exhibited significant degeneration, followed by morphological and molecular recovery at 10 days, when neuronal and synaptic markers returned to control levels. Gene expression analyses revealed early upregulation of C-6, C-4, and C-2 sulfotransferases in the final stage. For the first time, the presence of dermatan 2,6 sulfate (D2,6S) and chondroitin 4 sulfate (C4S) in the cortex of the cerebral ganglion was described and 2,6 sulfate disaccharides were found to make up the majority of the NC, emphasizing their relationship with regeneration. A behavioral test revealed that co-injecting 3-AP and D2,6S restored the compromised siphon movements. Finally, ascidian DS epimerase (DSE) was most closely related to vertebrate DSE type 2, which is found in the brains of mammals. Together, these results indicate that specific glycosaminoglycan sulfation patterns are dynamically regulated during neural regeneration in ascidians. This study provides new insights into the molecules and strategies promoting neuroregeneration in vertebrates and advances the field of regenerative medicine.