Pears Michael R, Salek Reza M, Palmer David N, Kay Graham W, Mortishire-Smith Russell J, Griffin Julian L
Department of Biochemistry, University of Cambridge, Cambridge, UK.
J Neurosci Res. 2007 Nov 15;85(15):3494-504. doi: 10.1002/jnr.21343.
The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal inherited neurodegenerative diseases in humans and animals distinguished by a common clinical pathology, characteristic storage body accumulation in cells, and gross brain atrophy. An (1)H NMR spectroscopy- and GC-MS-based metabolomic investigation of changes in the cerebellum, frontal and occipital lobes, and cerebrospinal fluid (CSF) of CLN6 NCL affected South Hampshire sheep charted changes from the preclinical state to advanced disease. Glutamine and succinate concentrations increased in all brain regions in affected sheep relative to controls, whereas concentrations of aspartate, acetate, glutamate, N-acetyl aspartate (NAA), and gamma-aminobutyric acid (GABA) decreased. Changes in the concentrations of inositols, NAA, and GABA were consistent with glial cell activation and neurodegeneration beginning in the frontal and occipital lobes, in agreement with previous histopathological data. Further metabolic deficits were defined in all regions at earlier time points, including the cerebellum, where very little neurological degeneration has been reported. Biochemical abnormalities in the CSF of affected sheep at 18-31 months include relative increases in lactate, acetate, tyrosine, and creatine/creatinine concentrations and decreases in myo- and scyllo-inositol and citrate concentrations. The changes detected in the CSF and brain tissue mirrored those previously apparent in NCL mouse models, suggesting that they are common to all NCLs. However, the changes in glutamate and glutamine concentrations in CSF occurred after clinical disease, indicating that any changes in glutamate/glutamine cycling occur as a consequence of the primary deficits associated with the NCLs.
神经元蜡样脂褐质沉积症（NCLs；巴滕病）是一组发生于人类和动物的致命性遗传性神经退行性疾病，其特征为具有共同的临床病理学表现、细胞内特征性储存体蓄积以及明显的脑萎缩。一项基于氢核磁共振波谱法（¹H NMR）和气相色谱 - 质谱联用（GC - MS）的代谢组学研究，对CLN6型NCL病影响的南汉普郡绵羊的小脑、额叶和枕叶以及脑脊液（CSF）中的变化进行了分析，描绘了从临床前期到疾病晚期的变化过程。与对照组相比，患病绵羊所有脑区的谷氨酰胺和琥珀酸浓度升高，而天冬氨酸、乙酸、谷氨酸、N - 乙酰天冬氨酸（NAA）和γ - 氨基丁酸（GABA）浓度降低。肌醇、NAA和GABA浓度的变化与额叶和枕叶开始出现的胶质细胞活化和神经退行性变一致，这与先前的组织病理学数据相符。在更早的时间点，包括小脑在内的所有区域都发现了进一步的代谢缺陷，而此前关于小脑的神经退行性变报道很少。患病绵羊在18 - 31个月时脑脊液中的生化异常包括乳酸、乙酸、酪氨酸和肌酸/肌酐浓度相对升高，以及肌醇和半乳糖肌醇及柠檬酸盐浓度降低。在脑脊液和脑组织中检测到的变化与先前在NCL小鼠模型中观察到的变化相似，表明这些变化在所有NCLs中都很常见。然而，脑脊液中谷氨酸和谷氨酰胺浓度的变化发生在临床疾病之后，这表明谷氨酸/谷氨酰胺循环的任何变化都是由与NCLs相关的原发性缺陷引起的。
