Shogo Oka

BACKGROUND: The human natural killer-1 (HNK-1) carbohydrate, a unique trisaccharide possessing sulfated glucuronic acid in a non-reducing terminus (HSO3-3GlcAß1-3Galß1-4GlcNAc-), is highly expressed in the nervous system and its spatiotemporal expression is strictly regulated. Mice deficient in the gene encoding a key enzyme, GlcAT-P, of the HNK-1 biosynthetic pathway exhibit almost complete disappearance of the HNK-1 epitope in the brain, significant reduction of long-term potentiation, and aberration of spatial learning and memory formation. In addition to its physiological roles in higher brain function, the HNK-1 carbohydrate has attracted considerable attention as an autoantigen associated with peripheral demyelinative neuropathy, which relates to IgM paraproteinemia, because of high immunogenicity. It has been suggested, however, that serum autoantibodies in IgM anti-myelin-associated glycoprotein (MAG) antibody-associated neuropathy patients show heterogeneous reactivity to the HNK-1 epitope. SCOPE OF REVIEW: We have found that structurally distinct HNK-1 epitopes are expressed in specific proteins in the nervous system. Here, we overview the current knowledge of the involvement of these HNK-1 epitopes in the regulation of neural plasticity and discuss the impact of different HNK-1 antigens of anti-MAG neuropathy patients. MAJOR CONCLUSIONS: We identified the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor subunit GluA2 and aggrecan as HNK-1 carrier proteins. The HNK-1 epitope on GluA2 and aggrecan regulates neural plasticity in different ways. Furthermore, we found the clinical relationship between reactivity of autoantibodies to the different HNK-1 epitopes and progression of anti-MAG neuropathy. GENERAL SIGNIFICANCE: The HNK-1 epitope is indispensable for the acquisition of normal neuronal function and can be a good target for the establishment of diagnostic criteria for anti-MAG neuropathy.

このたび，東京都健康長寿医療センター研究所副所長の遠藤玉夫先生が本年6月12日に日本学士院賞を受賞されました．誠に喜ばしく，心よりお祝い申し上げます．受賞タイトルは「福山型筋ジストロフィーを含めた糖鎖合成異常症の系統的な解明と新しい糖鎖の発見」で，神戸大学大学院医学研究科教授の戸田達史先生との共同受賞となりました．日本に多い福山型筋ジストロフィー症の原因遺伝子と発症に関わる新しい糖鎖の発見から，福山型およびその類縁疾患が系統的な糖鎖合成異常症であることを解明し，根本的な治療法開発への道を拓いたことが高く評価されました．

The human natural killer-1 (HNK-1) carbohydrate epitope, composed of a unique acidic trisaccharide HSO3-3GlcAβ1-3Galβ1-4GlcNAc-, is highly expressed in the nervous system. The HNK-1 epitope is found in N-linked and O-mannose-linked glycans of glycoproteins and also in some glycolipids (Chou et al. 1986 Kouno et al. 2011 Yuen et al. 1997). Intriguingly, limited glycoproteins are modified with the HNK-1 epitope such as the immunoglobulin-superfamily cell adhesion molecules (NCAM, L1, MAG, P0, etc.), extracellular matrix proteins (tenascin-R, phosphacan, etc.), and a glutamate receptor subunit (GluA2) (Kizuka and Oka 2012), suggesting that the HNK-1 glycan is expressed in a tightly regulated manner in the neural cells. As for physiological function, HNK-1 glycan is required for memory and learning, revealed by studies using enzyme-deficient mice (Senn et al. 2002 Yamamoto et al. 2002 Yoshihara et al. 2009). The unique structure of the HNK-1 glycan is attributed to a sulfated GlcA residue that is rarely seen in other N-linked and O-mannose-linked glycans, and key enzymes for the biosynthesis are two glucuronyltransferases, GlcAT-P and GlcAT-S (B3GAT1 and 2, respectively), and a sulfotransferase, HNK-1ST (see Chap. 92, “Carbohydrate Sulfotransferase 10 (CHST10)"). In this chapter, enzymatic features of the two glucuronyltransferases are further described, which should help us to understand the functions and expression mechanisms of the HNK-1 glycan.

ポリシアル酸やHNK-1糖鎖は神経系の細胞接着分子に特徴的に見られる糖鎖であり、その発現はさまざまな生物学的な現象と対応して厳密に制御されている。われわれはHNK-1糖鎖に関する研究を通して、その発現制御には糖鎖生合成に関わる酵素の発現量だけでなくリン脂質などの細胞膜環境や生合成酵素の複合体の形成が関わっていることを明らかにした。また、このような厳密な制御を受けている糖鎖が消失することによって、学習記憶などさまざまな神経機能に影響が見られることを見出している。(著者抄録)