Glycosphingolipids in murine neurodegenerative diseases

本研究的目的是开发一种有效的治疗神经节苷脂储存疾病的终生疗法。 神经节苷脂增多症是一组无法治愈的神经退行性疾病，涉及 神经节苷脂GM1或GM2存在于溶酶体内。GM1神经节苷脂沉积症是由酸性b-神经节苷脂基因缺陷引起的 分解神经节苷脂GM1的半乳糖苷酶，而桑德霍夫病(SD)是由基因引起的 分解神经节苷脂gm2的b-氨基己糖苷酶b亚单位缺乏。神经节苷脂在体内的蓄积 这些疾病会导致神经元死亡、炎症和进行性神经退化。我们的 研究将涉及疾病管理的多样化和互补性方法。这项研究将 评价NB-DGJ作为一种底物减少疗法，神经干细胞(NSCs)作为交叉矫正 治疗，以及作为抗炎治疗的热量限制(CR)。NB-DGJ可降低糖化血红蛋白生成速率 鞘脂(GSL)的生物合成，从而抵消了分解代谢受损的速度。NSC提供 缺少溶酶体酶从而减少GSL的储存，而CR通过影响 中枢神经系统炎症过程。目的1测定Nb-DGJ对小鼠GSL组成的影响。 正常小鼠和GM1神经节苷脂增多症和SD突变型小鼠的出生后脑。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的程度 合成抑制延迟神经节苷脂在中枢组织中的病理性储存，以及c)GSL的合成 抑制延缓储积症小鼠的髓鞘异常。Aim 2将评估治疗方案 神经干细胞(NSC)单独移植和与NB-DGJ联合移植在发育中的SD小鼠中的潜力。 我们假设NSCs将与和NB-DGJ协同作用，以减少GSLS的累积和 提供最大的治疗效果。目的3检测NB-DGJ对胚胎神经节苷脂的影响 接下来的子宫给药。这些研究将测试子宫内药物定时释放的可行性。 底物减少法治疗神经节苷脂沉积症。目标4将检验CR降低中枢神经系统的假设 炎症与CR和NB-DGJ在控制中枢炎症中协同作用，神经节苷脂 积聚和疾病进展。拟议的研究将提供以下方面的重要信息 神经节苷脂蓄积性疾病的联合治疗将对临床有一定的借鉴意义。

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.