Kaidonis Xenia, Byers Sharon, Ranieri Enzo, Sharp Peter, Fletcher Janice, Derrick-Roberts Ainslie
Department of Genetics and Molecular Pathology, SA Pathology (CYWHS site), North Adelaide, South Australia, Australia; Department of Genetics, University of Adelaide, Adelaide, South Australia, Australia.
Department of Genetics and Molecular Pathology, SA Pathology (CYWHS site), North Adelaide, South Australia, Australia; Department of Genetics, University of Adelaide, Adelaide, South Australia, Australia; Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia.
Mol Genet Metab. 2016 Jun;118(2):100-10. doi: 10.1016/j.ymgme.2016.04.002. Epub 2016 Apr 13.
Mucopolysaccharidosis IIIA is a heritable neurodegenerative disorder resulting from the dysfunction of the lysosomal hydrolase sulphamidase. This leads to the primary accumulation of the complex carbohydrate heparan sulphate in a wide range of tissues and the secondary neuronal storage of gangliosides GM2 and GM3 in the brain. GM2 storage is associated with CNS deterioration in the GM2 gangliosidosis group of lysosomal storage disorders and may also contribute to MPS CNS disease. N-butyldeoxynojirimycin, an inhibitor of ceramide glucosyltransferase activity and therefore of ganglioside synthesis, was administered to MPS IIIA mice both prior to maximal GM2 and GM3 accumulation (early treatment) and after the maximum level of ganglioside had accumulated in the brain (late treatment) to determine if behaviour was altered by ganglioside level. Ceramide glucosyltransferase activity was decreased in both treatment groups; however, brain ganglioside levels were only decreased in the late treatment group. Learning in the water cross maze was improved in both groups and the innate fear response was also restored in both groups. A reduction in the expression of inflammatory gene Ccl3 was observed in the early treatment group, while IL1β expression was reduced in both treatment groups. Thus, it appears that NB-DNJ elicits a transient decrease in brain ganglioside levels, some modulation of inflammatory cytokines and a functional improvement in behaviour that can be elicited both before and after overt neurological changes manifest.
NB-DNJ improves learning and restores the innate fear response in MPS IIIA mice by decreasing ceramide glucosyltransferase activity and transiently reducing ganglioside storage and/or modulating inflammatory signals.
黏多糖贮积症IIIA型是一种遗传性神经退行性疾病，由溶酶体水解酶硫酸酰胺酶功能障碍引起。这导致复合碳水化合物硫酸乙酰肝素在多种组织中初步蓄积，以及神经节苷脂GM2和GM3在大脑中继发神经元蓄积。GM2蓄积与溶酶体贮积症GM2神经节苷脂沉积症组的中枢神经系统恶化有关，也可能导致黏多糖贮积症的中枢神经系统疾病。N-丁基脱氧野尻霉素是一种神经酰胺葡糖基转移酶活性抑制剂，因此也是神经节苷脂合成抑制剂，在最大量GM2和GM3蓄积之前（早期治疗）和大脑中神经节苷脂蓄积达到最大水平之后（晚期治疗）给予黏多糖贮积症IIIA型小鼠，以确定行为是否因神经节苷脂水平而改变。两个治疗组的神经酰胺葡糖基转移酶活性均降低；然而，只有晚期治疗组的脑内神经节苷脂水平降低。两个组在水迷宫中的学习能力均得到改善，并且两个组的先天恐惧反应也都恢复。早期治疗组观察到炎症基因Ccl3的表达降低，而两个治疗组的IL1β表达均降低。因此，似乎N-丁基脱氧野尻霉素可引起脑内神经节苷脂水平短暂降低、炎症细胞因子的一些调节以及行为功能改善，这在明显的神经学变化出现之前和之后均可引发。
N-丁基脱氧野尻霉素通过降低神经酰胺葡糖基转移酶活性、短暂减少神经节苷脂贮积和/或调节炎症信号来改善黏多糖贮积症IIIA型小鼠的学习能力并恢复先天恐惧反应。
