Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Department of Biological Chemistry, Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Biochim Biophys Acta Gen Subj. 2017 Oct;1861(10):2455-2461. doi: 10.1016/j.bbagen.2017.06.025. Epub 2017 Jul 12.
The human natural killer-1 (HNK-1) carbohydrate, a unique trisaccharide possessing sulfated glucuronic acid in a non-reducing terminus (HSO-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.
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.
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.
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.
人类自然杀伤细胞-1（HNK-1）碳水化合物是一种独特的三糖，在非还原末端含有硫酸化葡萄糖醛酸（HSO3GlcAβ1-3Galβ1-4GlcNAc-），在神经系统中高度表达，其时空表达受到严格调控。缺乏 HNK-1 生物合成途径关键酶编码基因 GlcAT-P 的小鼠，大脑中的 HNK-1 表位几乎完全消失，长时程增强显著减少，空间学习和记忆形成异常。除了在大脑高级功能中的生理作用外，HNK-1 碳水化合物作为一种与周围脱髓鞘神经病相关的自身抗原，由于其高度免疫原性，引起了相当大的关注，该疾病与 IgM 副蛋白血症有关。然而，有人认为，IgM 抗髓鞘相关糖蛋白（MAG）抗体相关神经病患者的血清自身抗体对 HNK-1 表位表现出异质性反应。
我们发现，神经系统中特定蛋白质表达结构不同的 HNK-1 表位。在这里，我们概述了这些 HNK-1 表位在神经可塑性调节中的作用，并讨论了不同 MAG 神经病患者的 HNK-1 抗原的影响。
我们鉴定了 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体亚基 GluA2 和聚集蛋白为 HNK-1 载体蛋白。GluA2 和聚集蛋白上的 HNK-1 表位以不同的方式调节神经可塑性。此外，我们发现自身抗体对不同 HNK-1 表位的反应性与抗 MAG 神经病的进展之间存在临床关系。
HNK-1 表位对获得正常神经元功能是必不可少的，并且可以作为建立抗 MAG 神经病诊断标准的良好靶点。
