GLYCOSPHINGOLIPIDS IN MURINE NEURODEGENERATIVE DISEASES

描述(摘自申请者摘要)：鞘糖脂(GSLS)是 富含质膜，由神经节苷脂和中性 鞘糖脂。神经节苷脂储存的婴儿期和幼年期 疾病(GM1和GM2神经节苷脂沉积症)表现为严重的精神和运动 出生后头几年内的退化主要是由于神经节苷脂 在大脑中积累。由于复杂的GSLs在 哺乳动物胚胎发育的早期阶段，与 神经节苷脂的积累将在胎儿发育期间开始，并将恶化 在出生后的大脑中。因此，有效的治疗策略需要 积极的早期干预。此应用程序的目标是评估 NB-DGJ对胚胎发育过程中神经鞘糖脂代谢的影响 出生后大脑发育。NB-DGJ(N-丁基脱氧半乳糖苷)是一种 关键的神经酰胺特异性糖基转移酶的水溶性抑制物 神经鞘糖脂(GSL)生物合成酶。初步调查结果表明 NB-DGJ可以抑制GSL的生物合成而不改变活性或 器官发生期培养小鼠全胚胎的形态发生。此外， 我们的合作者表明，Nb-DGJ的结构异构体可以阻止 溶酶体在成年Tay-Sachs小鼠体内的储存并可降低神经功能 幼年桑德霍夫病小鼠的异常。没有前科 Nb-DGJ对小鼠牙周膜GSL成分及形态发生影响的研究 哺乳动物胚胎在子宫内或在出生后早期大脑中生长的胚胎 发展。这项研究将第一次检验：1) NB-DGJ对小鼠胚胎和出生后脑GSL组成的影响 2)NB-DGJ治疗对胚胎和胚胎的影响 出生后脑发育，以及3)胚胎和出生后NB-DGJ 治疗对大脑发育、神经化学和 行为。GSLS的含量和分布将在神经和 对照组和NB-DNJ处理组小鼠的非神经组织。胚胎和出生后 大脑发育将从形态、组织学和 生化测量。因为人类没有有效的治疗方法 神经节苷脂储存疾病，拟议的研究可能提供一种新的治疗方法 对这些神经退行性疾病进行早期干预。

DESCRIPTION (From the Applicant's Abstract): Glycosphingolipids (GSLs) are enriched in plasma membranes and comprise the gangliosides and the neutral glycosphingolipids. The infantile and juvenile forms of the ganglioside storage diseases (GM1 and GM2 gangliosidoses) present with severe mental and motor degeneration within the first few years of birth due largely to ganglioside accumulation in the brain. Since complex GSLs are actively synthesized during early stages of mammalian embryonic development, neuropathology associated with ganglioside accumulation will commence during fetal development and will worsen in the postnatal brain. An effective treatment strategy would therefore require aggressive early intervention. The objective of this application is to evaluate the effects of NB-DGJ on glycosphingolipid metabolism during embryonic and postnatal brain development. NB-DGJ (N-butyldeoxygalactonojirimycin) is a water-soluble inhibitor of the ceramide specific glucosyltransferase, a key enzyme for glycosphingolipid (GSL) biosynthesis. Preliminary findings indicate that NB-DGJ can inhibit GSL biosynthesis without altering viability or morphogenesis in the organogenesis stage cultured whole mouse embryo. Moreover, our collaborators showed that a structural isomer of NB-DGJ could prevent lysosomal storage in adult Tay-Sachs mice and could reduce neurological abnormalities in juvenile Sandhoff disease mice. There have been no prior studies on the effects of NB-DGJ on the GSL composition and morphogenesis in the mammalian embryo growing in utero or during early postnatal brain development. This research will examine for the first time: 1) the effects of NB-DGJ on the GSL composition of embryonic and postnatal brains in mouse models of the gangliosidoses, 2) the influence of NB-DGJ treatment on embryonic and postnatal brain development, and 3) whether embryonic and postnatal NB-DGJ treatment has long-lasting effects on brain development, neurochemistry, and behavior. The content and distribution of GSLs will be measured in neural and nonneural tissues of control and NB-DNJ-treated mice. Embryonic and postnatal brain development will be assessed from morphological, histological, and biochemical measurements. Since there are no effective treatments for human ganglioside storages disease, the proposed research could offer a novel therapy for the early intervention of these neurodegenerative disorders.