Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice
Interferon beta induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice
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DOI：
10.1093/brain/awt061
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发表时间：
2013-06-01
期刊：
影响因子：
14.5
通讯作者：
Sittler, Annie
中科院分区：
文献类型：
--
作者：
Chort, Alice;Alves, Sandro;Sittler, Annie
我们先前在脊髓小脑性共济失调7的细胞模型中表明，干扰素β诱导PML蛋白的表达和PML蛋白核体的形成，这些核体降解突变型共济失调蛋白7，这表明用于治疗多发性硬化的细胞因子可能对脊髓小脑性共济失调7具有治疗价值。我们现在表明，干扰素β也诱导PML依赖性清除共济失调蛋白7在临床前模型，SCA 7（266 Q/5 Q）敲入小鼠，并改善运动功能。有趣的是，小鼠中突变型共济失调蛋白7的存在本身诱导内源性干扰素β及其受体的表达。对两名脊髓小脑性共济失调患者大脑的免疫组织学研究证实，这些改变也是由人类疾病引起的。在基因敲入小鼠中，每周三次腹腔注射β干扰素，β干扰素与其在浦肯野细胞和其他细胞中的受体一起内化，并转移到细胞核中。治疗诱导PML蛋白表达和PML蛋白核体的形成，并减少神经元核内包涵体中的突变型共济失调蛋白7，这是该疾病的标志。在脑或内脏中未观察到反应性神经胶质增生或其他毒性体征。SCA 7（266 Q/5 Q）基因敲入小鼠的表现在对小脑功能敏感的两个行为测试中显著改善：运动功能的Locotronic（R）测试和平衡、运动协调和精细运动的Beam Walking测试，其在脊髓小脑性共济失调7患者中受到影响。除了运动功能障碍之外，SCA 7（266 Q/5 Q）小鼠在视网膜中呈现与患者中一样的异常：通过干扰素β治疗减少的共济失调蛋白7阳性神经元核内包涵体。最后，由于SCA 7（266 Q/5 Q）小鼠小脑中不发生神经元死亡，我们在表达突变型共济失调蛋白7的原代细胞培养物中显示干扰素β治疗可改善浦肯野细胞存活。
We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia 7. We now show that interferon beta also induces PML-dependent clearance of ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7 in the mice induces itself the expression of endogenous interferon beta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans. Interferon beta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic (R) Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant ataxin 7 that interferon beta treatment improves Purkinje cell survival.