Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis.
Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis.
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DOI：
10.1371/journal.pgen.1006846
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发表时间：
2017-07
期刊：
影响因子：
4.5
通讯作者：
Dragatsis I
中科院分区：
文献类型：
--
作者：
Dietrich P;Johnson IM;Alli S;Dragatsis I
亨廷顿病（Huntington 'sDisease，HD）是一种以认知、行为和运动功能障碍为特征的常染色体显性遗传的进行性神经退行性疾病。HD是由HD基因外显子1中的CAG重复扩增引起的，其被翻译成编码蛋白亨廷顿蛋白（HTT）中的扩增的多聚谷氨酰胺段。虽然HD最显著的神经病理学发生在纹状体，但其他脑区也受到影响，并在HD病理学中发挥重要作用。迄今为止，还没有治愈HD的方法，最近已经启动了旨在沉默HTT表达的策略，作为HD的可能治疗方法。然而，HTT在成人大脑中的基本功能目前尚不清楚，因此持续抑制HTT表达的后果是不可预测的，并且可能是有害的。使用Cre-loxP系统的重组，我们有条件地失活小鼠HD基因同源物在3，6和9个月大。在这里，我们表明，在成年小鼠的行为缺陷，进行性神经病理学变化，包括双侧丘脑钙化，并改变脑铁稳态的Htt表达的消除。亨廷顿氏病是一种遗传性疾病，其特征是进行性认知、行为和运动功能障碍。通常第一个症状出现在40岁左右，并在症状出现后15-20年内导致死亡。迄今为止，还没有治愈亨廷顿氏病的方法，目前的治疗策略只是治标不治本，远远不是最佳的。基因沉默是目前治疗亨廷顿病最有吸引力的方法。然而，由于正常和突变亨廷顿蛋白（亨廷顿氏病基因的蛋白产物）仅在多聚谷氨酰胺长度上不同，除非计划等位基因特异性沉默，否则正常亨廷顿蛋白（即神经保护性）也将失活，其影响未知。为了解决这些问题，我们研究了成年后正常亨廷顿功能消除的后果。总之，我们的研究表明，亨廷顿蛋白在脑铁稳态中起作用，并且亨廷顿蛋白在成年小鼠中的消除导致行为缺陷和进行性神经病理学变化，包括双侧丘脑钙化。
Huntington’s Disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by cognitive, behavioral and motor dysfunctions. HD is caused by a CAG repeat expansion in exon 1 of the HD gene that is translated into an expanded polyglutamine tract in the encoded protein, huntingtin (HTT). While the most significant neuropathology of HD occurs in the striatum, other brain regions are also affected and play an important role in HD pathology. To date there is no cure for HD, and recently strategies aiming at silencing HTT expression have been initiated as possible therapeutics for HD. However, the essential functions of HTT in the adult brain are currently unknown and hence the consequence of sustained suppression of HTT expression is unpredictable and can potentially be deleterious. Using the Cre-loxP system of recombination, we conditionally inactivated the mouse HD gene homologue at 3, 6 and 9 months of age. Here we show that elimination of Htt expression in the adult mouse results in behavioral deficits, progressive neuropathological changes including bilateral thalamic calcification, and altered brain iron homeostasis. Huntington’s Disease is a genetic disorder characterized by progressive cognitive, behavioral and motor dysfunctions. Usually the first symptoms appear around 40 years of age, and lead to death within 15–20 years after the onset of symptoms. To date there is no cure for Huntington’s Disease, and current therapeutic strategies are only palliative, and far from optimal. Gene silencing currently appears as the most attractive approach for the treatment of Huntington’s Disease. However, since normal and mutant huntingtin (the protein product of the Huntington’s disease gene) differ only on the polyglutamine length, unless allele-specific silencing is planned, normal huntingtin (that is neuroprotective) will also be inactivated with unknown implications. To address these questions, we investigated the consequences of elimination of normal huntingtin function in adulthood. In summary, our studies show that huntingtin plays a role in brain iron homeostasis, and that elimination of huntingtin in the adult mouse results in behavioral deficits and progressive neuropathological changes including bilateral thalamic calcification.