GLYCOLIPID METABOLISM AND MOTOR NEURON DISEASE

肌萎缩侧索硬化症（ALS）是一种破坏性的， 运动神经元的退行性疾病（通常表现为 中年），导致肌肉萎缩、瘫痪和死亡。 以来 关于ALS的病因或确切发病机制知之甚少，我们 我提议检验这种疾病可能是由异常 鞘糖脂（GSL）（神经节苷脂）代谢。 我们将在结构上 描述在所有9例中已检测到的3种主要异常神经节苷脂 到目前为止检查的ALS脊髓，但不包括非ALS脊髓， 并将研究扩展到肌萎缩侧索硬化症的肌肉和运动神经元丰富的区域， 脑，包括神经节苷脂和含中性己糖胺 糖脂 结构分析需要结合薄层 色谱法、特异性糖苷酶、GLS-质谱法和特异性 克隆抗体 将与未受影响的GSL进行比较 大脑区域。 来自患有各种类型的GM 2-神经节苷脂沉积症的患者的成纤维细胞， 包括一名25岁的患者， N-乙酰-B-D-氨基葡萄糖苷酶B（Hex B）缺乏和典型的ALS样 将测定症状降解这些神经节苷脂的能力。 Hex B α或β链的多克隆抗体将用于 确定Hex B在这些细胞中是否合成不足，以及HeB B或a 新的同工酶在运动神经元中占优势。 最后，所有100个或更多 在芝加哥大学就诊的ALS患者将接受以下测试： Hex A和B水平和同工酶谱。 我们的长期目标是表明， ALS运动神经元中含有己糖胺的神经节苷脂导致 在溶酶体贮积病中观察到的神经元变性或 运动神经元发芽，导致神经运动功能逐渐丧失， 功能 这一发现将成为ALS治疗的基础。

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.