Animal models for glutaryl-CoA dehydrogenase deficiency.
Animal models for glutaryl-CoA dehydrogenase deficiency.
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戊二酰辅酶A脱氢酶缺乏症的动物模型。
DOI：
10.1023/b:boli.0000045763.52907.5e
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发表时间：
2004
影响因子：
4.2
通讯作者：
Kölker,S
中科院分区：
文献类型：
--
作者：
Koeller,DM;Sauer,S;Wajner,M;deMello,CF;Goodman,SI;Woontner,M;Mühlhausen,C;Okun,JG;Kölker,S
总结：体外研究表明，兴奋性毒性细胞损伤是戊二酰辅酶A脱氢酶（GCDH）缺乏症急性纹状体损伤的潜在机制。据信是由积累的有机酸3-羟基谷氨酸（3-OH-GA）和较小程度的谷氨酸（GA）诱导的谷氨酸能和GABA能神经传递失衡引起的。将3-OH-GA和GA立体定位给药至大鼠纹状体证实了这些结果，但可能无法真正代表长期暴露于这些化合物的影响。为了更好地理解GCDH缺乏的病理生理学，已经利用了两种动物模型。通过在胚胎干细胞中进行基因靶向产生在所有组织中缺乏GCDH活性的小鼠。这些动物发展出人类疾病的特征性生化表型。在病理学上，这些小鼠具有与人类患者相似的弥漫性海绵状髓鞘病;然而，没有证据表明急性纹状体损伤或对由catastrophic或炎性细胞因子诱导的急性脑病敏感。一种天然存在的动物模型，食水果的埃及蝙蝠，缺乏肝脏和肾脏GCDH活性，但保留了大脑酶活性。像老鼠一样，这些蝙蝠发展出戊二酰辅酶A脱氢酶缺乏症的特征性生化表型，但缺乏明显的神经系统症状，如肌张力障碍。目前尚不清楚它们是否也会出现Gcdh缺陷小鼠中观察到的海绵状髓鞘病。否则，这些星座将表明，大脑GCDH缺乏是负责神经元损伤的发展。这两种啮齿动物模型中纹状体损伤的缺乏也可能与物种差异有关。然而，他们也强调了我们缺乏对其他因素的全面理解，这些因素可能调节神经元在GCDH缺乏症中积累3-OH-GA和GA的不稳定性。解开这些机制可能是理解这种独特疾病的病理生理学和神经保护策略发展的关键。
Summary:In vitrostudies suggest that excitotoxic cell damage is an underlying mechanism for the acute striatal damage in glutaryl‐CoA dehydrogenase (GCDH) deficiency. It is believed to result from an imbalance of glutamatergic and GABAergic neurotransmission induced by the accumulating organic acids 3‐hydroxyglutaric acid (3‐OH‐GA) and to a lesser extent glutaric acid (GA). Stereotaxic administration of 3‐OH‐GA and GA into the rat striatum have confirmed these results, but may not truly represent the effect of chronic exposure to these compounds. In an attempt to better understand the pathophysiology of GCDH deficiencyin vivo, two animal models have been utilized. A mouse that lacks GCDH activity in all tissues was generated by gene targeting in embryonic stem cells. These animals develop the characteristic biochemical phenotype of the human disease. Pathologically, these mice have a diffuse spongiform myelinopathy similar to that in human patients; however, there is no evidence for acute striatal damage or sensitivity to acute encephalopathy induced by catabolism or inflammatory cytokines. A naturally occurring animal model, the fruit‐eating batRousettus aegypticus, lacks hepatic and renal GCDH activity, but retains cerebral enzyme activity. Like the mouse, these bats develop the characteristic biochemical phenotype of glutaryl‐CoA dehydrogenase deficiency, but lack overt neurological symptoms such as dystonia. It is not known whether they also develop the spongiform myelinopathy seen in the Gcdh‐deficient mice. Otherwise, these constellations would suggest that cerebral GCDH deficiency is responsible for the development of neuronal damage. The lack of striatal damage in these two rodent models may also be related to species differences. However, they also highlight our lack of a comprehensive understanding of additional factors that might modulate the susceptibiliy of neurons to accumulating 3‐OH‐GA and GA in GCDH deficiency. Unravelling these mechanisms may be the key to understanding the pathophysiology of this unique disease and to the development of neuroprotective strategies.