CSGalNACT1, encoding chondroitin sulfate N-acetylgalactosaminyltransferase 1, is a key enzyme in the biosynthesis of sulfated glycosaminoglycans chondroitin and dermatan sulfate, initiating chondroitin sulfate (CS) chain biosynthesis on the GAG-protein linker region tetrasaccharide [2,3,6]. CS is a major component of extracellular matrix, and its synthesis pathway is crucial for various biological processes. Genetic models, such as knockout mice, have been valuable in studying CSGalNACT1's functions.

In T1KO (CSGalNACT1 knockout) mice, extensive axon regeneration occurs following spinal cord injury, and there is a loss of onset of ocular dominance plasticity, suggesting important roles for extracellular CS in neuronal plasticity and axon regeneration [1]. T1KO mice also show reduced CS amount in various brain regions and PNNs, along with behavioral abnormalities in tests like open-field, acoustic startle response, and social preference, indicating T1's importance for plasticity likely via regulation of CS-dependent PNNs [4]. In the context of experimental autoimmune encephalomyelitis, CSGalNACT1-KO mice show milder symptoms compared to wild-type mice, suggesting CS contributes to the induction phase of this disease [5]. Additionally, diabetic T1KO mice are more resistant to diabetic neuropathy, with more stable pericyte-endothelial cell interactions and less up-regulated Smad2/3 phosphorylation in the TGF-β signaling pathway [7].

In conclusion, CSGalNACT1 plays essential roles in multiple biological processes through its function in CS synthesis. The study of CSGalNACT1 KO mouse models has revealed its significance in neuronal plasticity, axon regeneration, immune-related neurological diseases, and diabetic neuropathy, providing insights into the underlying mechanisms and potential therapeutic targets for these conditions.

References:

1. Igarashi, Michihiro, Takeuchi, Kosei, Sugiyama, Sayaka. 2017. Roles of CSGalNAcT1, a key enzyme in regulation of CS synthesis, in neuronal regeneration and plasticity. In Neurochemistry international, 119, 77-83. doi:10.1016/j.neuint.2017.10.001. https://pubmed.ncbi.nlm.nih.gov/28987564/

2. Meyer, R, Schacht, S, Buschmann, L, Kurth, I, Elbracht, M. 2019. Biallelic CSGALNACT1-mutations cause a mild skeletal dysplasia. In Bone, 127, 446-451. doi:10.1016/j.bone.2019.07.016. https://pubmed.ncbi.nlm.nih.gov/31325655/

3. Mizumoto, Shuji, Janecke, Andreas R, Sadeghpour, Azita, Yamada, Shuhei, Vodopiutz, Julia. 2019. CSGALNACT1-congenital disorder of glycosylation: A mild skeletal dysplasia with advanced bone age. In Human mutation, 41, 655-667. doi:10.1002/humu.23952. https://pubmed.ncbi.nlm.nih.gov/31705726/

4. Yoshioka, Nozomu, Miyata, Shinji, Tamada, Atsushi, Takeuchi, Kosei, Igarashi, Michihiro. 2017. Abnormalities in perineuronal nets and behavior in mice lacking CSGalNAcT1, a key enzyme in chondroitin sulfate synthesis. In Molecular brain, 10, 47. doi:10.1186/s13041-017-0328-5. https://pubmed.ncbi.nlm.nih.gov/28982363/

5. Inada, Rino, Miyamoto, Katsuichi, Tanaka, Noriko, Igarashi, Michihiro, Kusunoki, Susumu. . Chondroitin sulfate N-acetylgalactosyltransferase-1 knockout shows milder phenotype in experimental autoimmune encephalomyelitis than in wild type. In Glycobiology, 31, 260-265. doi:10.1093/glycob/cwaa072. https://pubmed.ncbi.nlm.nih.gov/32839819/

6. Vodopiutz, Julia, Mizumoto, Shuji, Lausch, Ekkehart, Sugahara, Kazuyuki, Janecke, Andreas R. 2016. Chondroitin Sulfate N-acetylgalactosaminyltransferase-1 (CSGalNAcT-1) Deficiency Results in a Mild Skeletal Dysplasia and Joint Laxity. In Human mutation, 38, 34-38. doi:10.1002/humu.23070. https://pubmed.ncbi.nlm.nih.gov/27599773/

7. Ishiguro, Hajime, Ushiki, Takashi, Honda, Atsuko, Igarashi, Michihiro, Sone, Hirohito. 2024. Reduced chondroitin sulfate content prevents diabetic neuropathy through transforming growth factor-β signaling suppression. In iScience, 27, 109528. doi:10.1016/j.isci.2024.109528. https://pubmed.ncbi.nlm.nih.gov/38595797/