Groner Y, Elroy-Stein O, Avraham K B, Schickler M, Knobler H, Minc-Golomb D, Bar-Peled O, Yarom R, Rotshenker S
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Biomed Pharmacother. 1994;48(5-6):231-40. doi: 10.1016/0753-3322(94)90138-4.
Down's Syndrome (DS), the phenotypic expression of human trisomy 21, is presumed to result from overexpression of certain genes residing on chromosome 21 at the segment 21q22-the Down locus. The "housekeeping" enzyme CuZn-superoxide dismutase (CuZnSOD) is encoded by a gene from that region and its activity is elevated in DS patients. Moreover, the recent discovery that familial ALS is associated with mutations in the gene encoding CuZnSOD, focused attention on the entanglement of oxygen-free radicals in cell death and neuronal disorders. To investigate the involvement of CuZnSOD gene dosage in the etiology of the syndrome we have developed both cellular and animal models which enabled us to investigate the physiological consequences resulting from overexpression of the CuZnSOD gene. Rat PC12 cells expressing elevated levels of transfected human CuZnSOD gene were generated. These transformants (designated PC12-hSOD) closely resembled the parental cells in their morphology, growth rate, and response to nerve growth factor, but showed impaired neurotransmitter uptake. The lesion was localized to the chromaffin granule transport mechanism. These results show that elevation of CuZnSOD activity interferes with the transport of biogenic amines into chromaffin granules. Since neurotransmitter uptake plays an important role in many processes of the central nervous system, CuZnSOD gene-dosage may contribute to the neurobiological abnormalities of Down's Syndrome. As an approach to the development of an animal model for Down's Syndrome, several strains of transgenic mice which carry the human CuZnSOD gene have been prepared. These animals express the transgene as an active enzyme with increased activity from 1.6 to 6.0-fold in the brains of four transgenic strains and to an equal or lesser extent in several other tissues. To investigate the contribution of CuZnSOD gene dosage in the neuropathological symptoms of Down's Syndrome, we analyzed the tongue muscle of the transgenic-CuZnSOD mice. The tongue neuromuscular junctions (NMJ) in the transgenic animals exhibited significant pathological changes; withdrawal and destruction of some terminal axons and the development of multiple small terminals. The ratio of terminal axon area to postsynaptic membranes decreased, and secondary folds were often complex and hyperplastic. The morphological changes in the transgenic NMJ were similar to those previously seen in the transgenic NMJ and were similar to those previously seen in muscles of aging mice and rats as well as in tongue muscles of patients with Down's Syndrome. The findings suggest that CuZnSOD gene dosage is involved in the pathological abnormalities of tongue NMJ observed in Down's Syndrome patients.(ABSTRACT TRUNCATED AT 400 WORDS)
唐氏综合征（DS）是人类21三体的表型表达，据推测是由于位于21号染色体21q22区段（唐氏位点）上某些基因的过度表达所致。“管家”酶铜锌超氧化物歧化酶（CuZnSOD）由该区域的一个基因编码，其活性在DS患者中升高。此外，最近发现家族性肌萎缩侧索硬化症（ALS）与编码CuZnSOD的基因突变有关，这使得人们将注意力集中在细胞死亡和神经紊乱中氧自由基的纠缠上。为了研究CuZnSOD基因剂量在该综合征病因中的作用，我们建立了细胞和动物模型，使我们能够研究CuZnSOD基因过度表达所产生的生理后果。生成了表达转染人CuZnSOD基因水平升高的大鼠嗜铬细胞瘤（PC12）细胞。这些转化细胞（命名为PC12-hSOD）在形态、生长速率和对神经生长因子的反应方面与亲代细胞非常相似，但神经递质摄取受损。病变定位于嗜铬颗粒转运机制。这些结果表明，CuZnSOD活性的升高会干扰生物胺向嗜铬颗粒的转运。由于神经递质摄取在中枢神经系统的许多过程中起重要作用，CuZnSOD基因剂量可能导致唐氏综合征的神经生物学异常。作为开发唐氏综合征动物模型的一种方法，已经制备了几种携带人CuZnSOD基因的转基因小鼠品系。这些动物将转基因表达为一种活性酶，在四个转基因品系的大脑中活性增加1.6至6.0倍，在其他几个组织中的增加程度相同或较小。为了研究CuZnSOD基因剂量在唐氏综合征神经病理症状中的作用，我们分析了转基因CuZnSOD小鼠的舌肌。转基因动物的舌神经肌肉接头（NMJ）表现出明显的病理变化；一些终末轴突退缩和破坏，以及多个小终末的形成。终末轴突面积与突触后膜面积的比值降低，次级褶皱通常复杂且增生。转基因NMJ的形态变化与先前在转基因NMJ中观察到的变化相似，也与先前在衰老小鼠和大鼠的肌肉以及唐氏综合征患者的舌肌中观察到的变化相似。这些发现表明，CuZnSOD基因剂量与唐氏综合征患者中观察到的舌NMJ病理异常有关。（摘要截短至400字）
