GLYCOLIPID METABOLISM AND MOTOR NEURON DISEASE

肌萎缩侧索硬化症(ALS)是一种毁灭性的、进行性的 运动神经元退行性疾病(通常表现为 中年)，会导致肌肉萎缩、瘫痪和死亡。自.以来 我们对肌萎缩侧索硬化症的病因或确切发病机制知之甚少。 建议检验疾病可由异常引起的假设 神经节苷脂(GSL)代谢。我们将在结构上 描述已经在所有9个神经节苷脂中检测到的3个主要异常神经节苷脂 到目前为止检查过的ALS脊髓，但没有来自非ALS脊髓， 并将把搜索范围扩大到ALS肌肉和运动神经元丰富的区域 大脑，包括神经节苷脂和含有中性氨基己糖的 糖脂。结构分析将需要结合薄层 层析、特异性糖苷酶、GLS-MS和特异性 单克隆抗体。将与未受影响的GSL进行比较 大脑区域。 不同类型GM2神经节苷脂沉积症患者的成纤维细胞， 包括一名25岁的患者，患有之前未描述的特定疾病 N-乙酰-B-D-氨基葡萄糖苷酶B缺乏和典型的肌萎缩侧索硬化症样 症状将被分析以确定是否有能力降解这些神经节苷脂。 抗六角Bα链或β链的多克隆抗体将用于 确定是否在这些细胞中合成十六烷基硫酸酯B不足，以及是否Heb B或a 新的同工酶主要存在于运动神经元中。最后，全部100个或更多 在芝加哥大学技术年看到的ALS患者将接受 十六进制A和B的水平和同工酶模式。 我们的长期目标是表明某些不正常的积累 肌萎缩侧索硬化症运动神经元中含有氨基己糖的神经节苷脂导致 溶酶体储存性疾病中出现的神经元变性或 运动神经元萌发，导致神经运动进行性丧失 功能。这一发现将为肌萎缩侧索硬化症治疗奠定基础。

Amyotrophic lateral sclerosis (ALS) is a devastating, progrssive degenerative disease of motor neurons (typically manifesting itself in middle age), which results in muscle wasting, paralysis and death. Since very little is known about the cause or precise pathogenesis of ALS, we propose to test the hypothesis that the disease can result from abnormal glycosphingolipid (GSL) (ganglioside) metabolism. We will structurally characterize the 3 major abnormal gangliosides already detected in all 9 ALS spinal cords thus far examined, but absent from non-ALS spinal cords, and will extend the search to ALS muscle and motor neuron-rich regions of the brain, including both gangliosides and neutral hexosamine-containing glycolipids. Structural analysis will require a combination of thin-layer chromatography, specific glycosidases, GLS-mass-spectrometry and specific monoclonal antibodies. Comparison will be made with GSL from unaffected brain regions. Fibroblasts from patients with various types of GM2-gangliosidosis, including a 25 year-old patient with a previously undescribed specific deficiency of N-acetyl-B-D-glucosaminidase B (Hex B) and typical ALS-like symptoms will be assayed for ability to degrade these gangliosides. Polyclonal antibodies to Hex B Alpha- or Beta-chains will be used to determine if Hex B is undersynthesized in these cells and if Heb B or a novel isoenzyme predominates in motor neurons. Finally, all 100 or more ALS patients seen at the University of Chicago ech year will be tested for Hex A and B levels and isoenzyme patterns. Our long-term objective is to show that abnormal accumulation of certain hexosamine-containing gangliosides in ALS motor neurons results in the type of neuronal degeneration seen in lysosomal storage diseases or a failure in motor neuron sprouting, which leads to progressive loss of neuromotor function. Such a finding would form the basis for ALS therapy.