Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases
Brain urea increase is an early Huntington's disease pathogenic event observed in a prodromal transgenic sheep model and HD cases
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DOI：
10.1073/pnas.1711243115
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发表时间：
2017-12-26
影响因子：
11.1
通讯作者：
Snell, Russell G.
中科院分区：
文献类型：
--
作者：
Handley, Renee R.;Reid, Suzanne J.;Snell, Russell G.
神经退行性疾病亨廷顿氏病（HD）的典型特征是纹状体神经元的广泛损失以及中年期发作的衰弱性和进行性舞蹈病、痴呆和心理障碍。HD是由亨廷顿蛋白（HTT）基因中的CAG重复扩增引起的，翻译成亨廷顿蛋白中的延长的谷氨酰胺片段。除了致病突变之外，导致细胞功能障碍和死亡的致病机制还没有很好的定义。为了进一步描述HD中的早期分子事件，我们对来自表达人CAG扩增HTT cDNA转基因的一组5岁OVT 73系绵羊的纹状体组织进行RNA测序（RNA-seq）。我们的HD OVT 73绵羊是前驱模型，表现出最低限度的病理学，没有可检测到的神经元损失。我们发现尿素转运蛋白SLC 14 A1在OVT 73纹状体中的水平显著增加，沿着其他重要的渗透调节因子。进一步的研究显示，OVT 73纹状体和小脑中代谢产物尿素水平升高，与我们最近发表的HD病例死后人脑中尿素增加的观察结果一致。扩展这一发现，我们证明，死后人脑尿素水平升高，在一个更大的队列HD的情况下，包括那些与低级别的神经病理学（Vonsattel级0/1）。这种升高表明蛋白质催化剂增加，可能作为HD中普遍代谢缺陷的替代能量来源。已知由于尿素循环失调而导致的尿素和氨水平升高会导致神经功能损害。总之，我们的研究结果表明，尿素代谢异常可能是主要的生化破坏引发HD的神经发病机制。
The neurodegenerative disorder Huntington's disease (HD) is typically characterized by extensive loss of striatal neurons and the midlife onset of debilitating and progressive chorea, dementia, and psychological disturbance. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. The pathogenic mechanism resulting in cell dysfunction and death beyond the causative mutation is not well defined. To further delineate the early molecular events in HD, we performed RNA-sequencing (RNA-seq) on striatal tissue from a cohort of 5-y-old OVT73-line sheep expressing a human CAG-expansion HTT cDNA transgene. Our HD OVT73 sheep are a prodromal model and exhibit minimal pathology and no detectable neuronal loss. We identified significantly increased levels of the urea transporter SLC14A1 in the OVT73 striatum, along with other important osmotic regulators. Further investigation revealed elevated levels of the metabolite urea in the OVT73 striatum and cerebellum, consistent with our recently published observation of increased urea in postmortem human brain from HD cases. Extending that finding, we demonstrate that postmortem human brain urea levels are elevated in a larger cohort of HD cases, including those with low-level neuropathology (Vonsattel grade 0/1). This elevation indicates increased protein catabolism, possibly as an alternate energy source given the generalized metabolic defect in HD. Increased urea and ammonia levels due to dysregulation of the urea cycle are known to cause neurologic impairment. Taken together, our findings indicate that aberrant urea metabolism could be the primary biochemical disruption initiating neuropathogenesis in HD.