Gonzalez-Gomez I, Mononen I, Heisterkamp N, Groffen J, Kaartinen V
Department of Pathology, Childrens Hospital Los Angeles Research Institute and University of Southern California, School of Medicine, USA.
Am J Pathol. 1998 Oct;153(4):1293-300. doi: 10.1016/S0002-9440(10)65674-X.
Aspartylglycosaminuria (AGU) is one of the most common lysosomal storage disorders in humans. A mouse model for AGU has been recently generated through targeted disruption of the glycosylasparaginase gene, and at a young age the glycosyl asparaginase-deficient mice demonstrated many pathological changes found in human AGU patients (Kaartinen V, Mononen I, Voncken J-W, Gonzalez-Gomez I, Heisterkamp N, Groffen J: A mouse model for aspartylglycosaminuria. Nat Med 1996, 2:1375-1378). Our current findings demonstrate that after the age of 10 months, the general condition of null mutant mice gradually deteriorated. They suffered from a progressive motoric impairment and impaired bladder function and died prematurely. A widespread lysosomal hypertrophy in the central nervous system was detected. This neuronal vacuolation was particularly severe in the lateral thalamic nuclei, medullary reticular nuclei, vestibular nuclei, inferior olivary complex, and deep cerebellar nuclei. The oldest animals (20 months old) displayed a clear neuronal loss and gliosis, particularly in those regions, where the most severe vacuolation was found. The severe ataxic gait of the older mice was likely due to the dramatic loss of Purkinje cells, intensive astrogliosis and vacuolation of neurons in the deep cerebellar nuclei, and the severe vacuolation of the cells in vestibular and cochlear nuclei. The impaired bladder function and subsequent hydronephrosis were secondary to involvement of the central nervous system. These findings demonstrate that the glycosylasparaginase-deficient mice share many neuropathological features with human AGU patients, providing a suitable animal model to test therapeutic strategies in the treatment of the central nervous system effects in AGU.
天冬氨酰葡糖胺尿症（AGU）是人类最常见的溶酶体贮积症之一。最近通过靶向破坏糖基天冬酰胺酶基因建立了AGU小鼠模型，在幼年时，糖基天冬酰胺酶缺陷小鼠表现出许多在人类AGU患者中发现的病理变化（卡尔蒂宁V、莫诺宁I、冯肯J-W、冈萨雷斯-戈麦斯I、海斯特坎普N、格罗芬J：天冬氨酰葡糖胺尿症的小鼠模型。《自然医学》1996年，2：1375 - 1378）。我们目前的研究结果表明，10个月龄后，纯合突变小鼠的总体状况逐渐恶化。它们出现进行性运动障碍和膀胱功能受损，并过早死亡。在中枢神经系统中检测到广泛的溶酶体肥大。这种神经元空泡化在外侧丘脑核、延髓网状核、前庭核、下橄榄复合体和小脑深部核团中尤为严重。最年长的动物（20月龄）表现出明显的神经元丢失和胶质增生，特别是在那些发现最严重空泡化的区域。老年小鼠严重的共济失调步态可能是由于浦肯野细胞的大量丢失、小脑深部核团中神经元的强烈星形胶质细胞增生和空泡化，以及前庭核和耳蜗核细胞的严重空泡化。膀胱功能受损及随后的肾积水是中枢神经系统受累的继发表现。这些研究结果表明，糖基天冬酰胺酶缺陷小鼠与人类AGU患者具有许多神经病理学特征，为测试治疗AGU中枢神经系统效应的治疗策略提供了合适的动物模型。
