Subtle neurological and metabolic abnormalities in an Opa1 mouse model of autosomal dominant optic atrophy
Subtle neurological and metabolic abnormalities in an Opa1 mouse model of autosomal dominant optic atrophy
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DOI：
10.1016/j.expneurol.2009.09.026
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发表时间：
2009-12-01
影响因子：
5.3
通讯作者：
Wissinger, Bernd
中科院分区：
文献类型：
--
作者：
Alavi, Marcel V.;Fuhrmann, Nico;Wissinger, Bernd
普遍表达的基因OPA1是常染色体显性视神经萎缩（ADOA）的主要致病基因。这些患者表现为双侧视力下降，中央视野缺损和色觉受损，继发于视网膜神经节细胞（RGCs）的进行性丧失和视神经的退化。到目前为止，还不清楚为什么一个普遍表达的基因突变只影响RGCs和视神经。22个月大的Opa1动物按照Shirpa方案进行了全面检查。监测体重、食物摄入量和寿命。采用Rotarod跑步机实验评估神经肌肉功能。采用组织化学方法检测线粒体细胞色素c氧化酶（COX）活性，采用远程PCR方法检测线粒体dna完整性。Shirpa实验显示33%的Opa1小鼠出现震颤，52%的Opa1小鼠出现抓握反射异常。对照动物在加速Rotarod跑步机实验中表现良好，而Opa1小鼠表现明显差。与综合征性ADOA患者相比，骨骼肌纤维形态学正常，COX活性正常，未显示继发性mtDNA损伤的证据。我们还发现了体重的显著差异。我们的研究结果表明，OPA1突变不仅影响RGCs，还影响其他组织和细胞类型，尽管影响程度较小。我们特别发现了神经肌肉和代谢功能的缺陷。因此，我们希望鼓励临床医生对ADOA患者的眼外表现保持警惕。(C) 2009爱思唯尔公司版权所有。
The ubiquitously expressed gene OPA1 is the main disease causing gene for autosomal dominant optic atrophy (ADOA). These patients present with bilateral reduction in visual acuity, central visual field defects and impaired color vision, secondary to the progressive loss of retinal ganglion cells (RGCs) and subsequent degeneration of the optic nerve. Up to now, it is not clear why a mutation in a ubiquitously expressed gene affects only RGCs and the optic nerve.Twenty-two-month-old Opa1 animals underwent a full examination following the Shirpa protocol. Weight, food intake and life span were monitored. Rotarod treadmill experiments were performed to assess neuromuscular function. Limb skeletal muscle was evaluated morphologically, mitochondrial cytochrome c oxidase (COX) activity was studied histochemically and mtDNA integrity was determined by long-range PCR. The Shirpa test showed that 33% of the Opa1 mice suffered from tremor and 52% of the Opa1 animals showed an abnormal clutching reflex. Control animals performed well in the accelerating Rotarod treadmill experiment whereas the Opa1 mice performed significantly worse. Skeletal muscle fibers were morphologically normal, had normal COX activity and showed no evidence of secondary mtDNA damage in contrast to patients with syndromic ADOA. We also found a highly significant difference in body weight. Our results demonstrate that OPA1 mutations affect not only RGCs but also other tissues and cell types, though to a lesser extent. In particular we found deficits in both neuromuscular and metabolic function. We therefore want to encourage clinicians to be vigilant about to extra-ocular manifestations in ADOA patients. (C) 2009 Elsevier Inc. All rights reserved.