PNAS：科学家首次开发出研究肌萎缩侧索硬化症的小鼠模型

       近日，来自美国西北大学的研究人员通过研究首次开发出了肌萎缩侧索硬化症(ALS)痴呆小鼠的模型，这一突破型研究将可以帮助研究人员在显微水平下，去深入研究麻痹状态的活体小鼠的大脑结构，有望开发出治疗ALS的靶向药物，相关研究刊登于国际杂志PNAS上。

      相比单一患ALS来讲，患痴呆症的ALS患者的病情更为严重，因为疾病不光会严重影响患者的行为，而且会影响患者大脑的语言表达，使得患者出现中风症状。ALS在全球影响着至少35万人的健康，患者的平均生存期为3年。神经性障碍疾病往下发展就是神经元的退化，进而引发肌肉萎缩和语言、呼吸障碍，最终引发中风和死亡。（转化医学网360zhyx.com）

      本文系转化医学网原创翻译整理，欢迎转载！转载请注明来源并附原文链接。谢谢！

转化医学网推荐的原文摘要：

Dendritic spinopathy in transgenic mice expressing ALS/dementia-linked mutant UBQLN2
PNAS doi: 10.1073/pnas.1405741111
George H. Gorriea,1, Faisal Fectoa,b,1, Daniel Radzickic, Craig Weissc,d, Yong Shia, Hongxin Dongb,e, Hong Zhaia, Ronggen Fua, Erdong Liua, Sisi Lia, Hasan Arrata, Eileen H. Bigiof,g, John F. Disterhoftc, Marco Martinac, Enrico Mugnainih, Teepu Siddiquea,b,h,2, and Han-Xiang Denga,2
Mutations in the gene encoding ubiquilin2 (UBQLN2) cause amyotrophic lateral sclerosis (ALS), frontotemporal type of dementia, or both. However, the molecular mechanisms are unknown. Here, we show that ALS/dementia-linked UBQLN2P497H transgenic mice develop neuronal pathology with ubiquilin2/ubiquitin/p62-positive inclusions in the brain, especially in the hippocampus, recapitulating several key pathological features of dementia observed in human patients with UBQLN2 mutations. A major feature of the ubiquilin2-related pathology in these mice, and reminiscent of human disease, is a dendritic spinopathy with protein aggregation in the dendritic spines and an associated decrease in dendritic spine density and synaptic dysfunction. Finally, we show that the protein inclusions in the dendritic spines are composed of several components of the proteasome machinery, including UbG76V–GFP, a representative ubiquitinated protein substrate that is accumulated in the transgenic mice. Our data, therefore, directly link impaired protein degradation to inclusion formation that is associated with synaptic dysfunction and cognitive deficits. These data imply a convergent molecular pathway involving synaptic protein recycling that may also be involved in other neurodegenerative disorders, with implications for development of widely applicable rational therapeutics.