Glycosphingolipids in murine neurodegenerative diseases

本研究的目的是开发一种有效的终身治疗神经节苷脂储存病。 神经节苷脂沉积症是一组无法治愈的神经退行性疾病， 溶酶体中的神经节苷脂GM 1或GM 2。GM 1神经节苷脂沉积症是由于遗传性缺乏酸性B- 半乳糖苷酶分解代谢神经节苷脂GM 1，而桑德霍夫病（SD）是由遗传性 分解代谢神经节苷脂GM 2的b-氨基己糖苷酶B亚单位缺乏。神经节苷脂蓄积 这些疾病导致神经元死亡、炎症和进行性神经功能恶化。我们 研究将涉及多种互补的疾病管理方法。这项研究将 评估NB-DGJ作为底物减少疗法，神经干细胞（NSC），作为交叉校正 治疗，以及作为抗炎治疗的热量限制（CR）。NB-DGJ降低糖基化速率， 鞘脂（GSL）生物合成，从而平衡受损的catalysts速率。NSC提供了 缺少溶酶体酶，从而减少GSL储存，而CR通过影响 CNS炎症过程。目的1将确定NB-DGJ对GSL组成的影响， 正常小鼠和GM 1神经节苷脂沉积症和SD突变体的出生后大脑。这一目标将决定：a） NB-DGJ治疗后脑神经节苷脂恢复的时间和程度，B）GSL 合成抑制延缓CNS组织中病理性神经节苷脂蓄积，和c）GSL合成是否 抑制延缓了胆积症小鼠中的髓鞘异常。目标2将评估治疗 在发育中的SD小鼠中单独和与NB-DGJ一起移植神经干细胞（NSC）的潜力。 我们假设NSC将与NB-DGJ协同作用以减少GSL的积累， 提供最大的治疗效果。目的3：探讨NB-DGJ对胚胎神经节苷脂的影响 子宫内给药后。这些研究将测试子宫内定时药物释放的可行性 GM 1神经节苷脂沉积症的底物减少疗法。目的4将检验CR降低CNS的假设 炎症，CR和NB-DGJ在控制CNS炎症、神经节苷脂 积累和疾病进展。拟议的研究将提供以下方面的重要信息： 神经节苷脂沉积病的组合疗法，并将具有临床转化效益。

The objective of this research is to develop an effective life long therapy for ganglioside storage diseases. The gangliosidoses are a group of incurable neurodegenerative diseases involving storage of either ganglioside GM1 or GM2 in lysosomes. GM1 gangliosidosis arises from a genetic deficiency of the acid b- galactosidase that catabolizes ganglioside GM1, whereas Sandhoff disease (SD) arises from genetic deficiency in the b-hexosaminidase b subunit that catabolizes ganglioside GM2. Ganglioside accumulation in these diseases leads to neuronal death, inflammation, and progressive neurological deterioration. Our studies will involve diverse and complimentary approaches for disease management. This research will evaluate NB-DGJ as a substrate reduction therapy, neural stem cells (NSCs), as across-correctional therapy, and caloric restriction (CR) as an anti-inflammatory therapy. NB-DGJ decreases the rate of glyco- sphingolipid (GSL) biosynthesis thereby counterbalancing an impaired rate of catabolism. NSCs provide the missing lysosomal enzyme thereby reducing GSL storage, whereas CR improves health through effects on CNS inflammatory processes. Aim 1will determine the effects of NB-DGJ on the GSL composition of postnatal brains in normal mice and in the GM1 gangliosidosis and SD mutants. This aim will determine, a) the timing and extent of brain ganglioside recovery following NB-DGJ treatment, b) the extent to which GSL synthesis inhibition delays pathological ganglioside storage in CNS tissues, and c) whether GSL synthesis inhibition delays myelin abnormalities in the storage disease mice. Aim 2 will evaluate the therapeutic potential of neural stem cell (NSC) transplantation alone and together with NB-DGJ in developing SD mice. We hypothesize that NSCs will act synergistically with and NB-DGJ to reduce accumulating GSLs and provide maximal therapeutic effect. Aim 3 will examine the influence of NB-DGJ on embryo gangliosides following in utero administration. These studies will test the feasibility of timed drug release for in utero substrate reduction therapy for GM1 gangliosidosis. Aim 4 will test the hypothesis that CR reduces CNS inflammation and that CR and NB-DGJ act synergistically in managing CNS inflammation, ganglioside accumulation, and disease progression. The proposed studies will provide essential information on combinatorial therapies for the ganglioside storage diseases and will have translational benefit to the clinic.