Liu Y, Hoffmann A, Grinberg A, Westphal H, McDonald M P, Miller K M, Crawley J N, Sandhoff K, Suzuki K, Proia R L
Section on Biochemical Genetics, Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8138-43. doi: 10.1073/pnas.94.15.8138.
The GM2 activator deficiency (also known as the AB variant), Tay-Sachs disease, and Sandhoff disease are the major forms of the GM2 gangliosidoses, disorders caused by defective degradation of GM2 ganglioside. Tay-Sachs and Sandhoff diseases are caused by mutations in the genes (HEXA and HEXB) encoding the subunits of beta-hexosaminidase A. The GM2 activator deficiency is caused by mutations in the GM2A gene encoding the GM2 activator protein. For degradation of GM2 ganglioside by beta-hexosamindase A, the GM2 activator protein must participate by forming a soluble complex with the ganglioside. In each of the disorders, GM2 ganglioside and related lipids accumulate to pathologic levels in neuronal lysosomes, resulting in clinically similar disorders with an onset in the first year of life, progressive neurodegeneration, and death by early childhood. We previously have described mouse models of Tay-Sachs (Hexa -/-) and Sandhoff (Hexb -/-) diseases with vastly different clinical phenotypes. The Hexa -/- mice were asymptomatic whereas the Hexb -/- mice were severely affected. Through gene disruption in embryonic stem cells we now have established a mouse model of the GM2 activator deficiency that manifests an intermediate phenotype. The Gm2a -/- mice demonstrated neuronal storage but only in restricted regions of the brain (piriform, entorhinal cortex, amygdala, and hypothalamic nuclei) reminiscent of the asymptomatic Tay-Sachs model mice. However, unlike the Tay-Sachs mice, the Gm2a -/- mice displayed significant storage in the cerebellum and defects in balance and coordination. The abnormal ganglioside storage in the Gm2a -/- mice consisted of GM2 with a low amount of GA2. The results demonstrate that the activator protein is required for GM2 degradation and also may indicate a role for the GM2 activator in GA2 degradation.
GM2激活蛋白缺乏症（也称为AB变异型）、泰-萨克斯病和桑德霍夫病是GM2神经节苷脂贮积症的主要形式，这些疾病是由GM2神经节苷脂降解缺陷引起的。泰-萨克斯病和桑德霍夫病是由编码β-己糖胺酶A亚基的基因（HEXA和HEXB）发生突变所致。GM2激活蛋白缺乏症是由编码GM2激活蛋白的GM2A基因发生突变引起的。为了使β-己糖胺酶A降解GM2神经节苷脂，GM2激活蛋白必须通过与神经节苷脂形成可溶性复合物来参与。在每种疾病中，GM2神经节苷脂和相关脂质在神经元溶酶体中积聚至病理水平，导致临床上相似的疾病，在出生后第一年发病，进行性神经变性，并在幼儿期死亡。我们之前已经描述了具有截然不同临床表型的泰-萨克斯病（Hexa-/-）和桑德霍夫病（Hexb-/-）的小鼠模型。Hexa-/-小鼠无症状，而Hexb-/-小鼠受到严重影响。通过胚胎干细胞中的基因破坏，我们现在建立了一种表现出中间表型的GM2激活蛋白缺乏症小鼠模型。Gm2a-/-小鼠表现出神经元贮积，但仅在大脑的特定区域（梨状区、内嗅皮质、杏仁核和下丘脑核），这让人想起无症状的泰-萨克斯病模型小鼠。然而，与泰-萨克斯病小鼠不同，Gm2a-/-小鼠在小脑中表现出明显的贮积，并且在平衡和协调方面存在缺陷。Gm2a-/-小鼠中异常的神经节苷脂贮积由含有少量GA2的GM2组成。结果表明，激活蛋白是GM2降解所必需的，也可能表明GM2激活蛋白在GA2降解中起作用。
